PGD2 receptor antagonistic pharmaceutical compositions

ABSTRACT

Compounds of the general formula (I) which are metabolically stable and have an antagonistic activity against PGD 2  receptor:
 
                 
 
 
 
wherein Y is bicyclic ring; R 1  is optionally substituted heteroaryl; R 2  is hydrogen, etc.; R 3  is —CH 2 —CH 2 —CH 2 —CH 2 —CH═CH—COOR 4 , —CH 2 —CH 2 —CH 2 —CH 2 —X 1 —CH 2 —COOR 4 , —CH 2 —CH═CH—CH 2 —X 1 —CH 2 —COOR 4  or —CH 2 —CH 2 —CH 2 —COOR 4 ; R 4  is hydrogen, etc.; X 1  is —O—, etc.

This application is the national phase of International Application No. PCT/JP01/09435, filed Oct. 26, 2001, published in a non-English language.

TECHNICAL FIELD

This invention relates to a bicyclic amide derivative, an antagonist against PGD₂ receptor, and a pharmaceutical composition comprising the same.

BACKGROUND ART

As a pharmaceutical composition comprising an antagonist against PGD₂ receptor, a compound of the formula:

  wherein Y is bicyclic ring and R is phenyl etc., was described in WO 97/00853 (International publication date: Jan. 1, 1997).

On the other hand, it was disclosed that 3-oxa-derivatives were prepared as metabolically stable TXA₂/PGH₂ receptor antagonists in Bioorganic & Medicinal Chemistry Letters, Vol. 2, No. 9, pp. 1069-1072, 1992. The active value of the compound was only described but the metabolic stability has not been described in the literature.

  wherein, Z is p-fluorophenyl; Rω is benzenesulfonamino and the like.

Furthermore, it was reported in PROSTAGLANDINS, 1986, 31, 95 that ILOPROST, PGI₂ mimetics was stabilized metabolically by converting to the 3-oxa-derivative. But, remaining activity of each compound was only compared under a presence of the metabolic enzyme of a rat and the metabolic stability did not mentioned.

DISCLOSURE OF INVENTION

The present inventors have carried out the structure modification research on α chain of a pharmaceutical composition comprising an antagonist against PGD₂ receptor described in WO97/00853, found out a metabolically stable antagonist against PGD₂ receptor and have completed the present invention.

The present invention provides:

-   (1) a compound represented by the formula (I):           wherein       -   R¹ is optionally substituted heteroaryl; -   R² is hydrogen or alkyl; -   R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴,     —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; -   R⁴ is hydrogen or alkyl; -   X¹ is —O— or —S—,     a prodrug, a pharmaceutically acceptable salt or a solvate thereof, -   (2) a compound as described in (1), wherein       -    a prodrug, a pharmaceutically acceptable salt or a solvate thereof, -   (3) a compound as described in (1) or (2), wherein R¹ is optionally     substituted thienyl, optionally substituted benzothienyl, optionally     substituted furyl, optionally substituted benzofuryl, optionally     substituted pyrrolyl, optionally substituted thienopyrrolyl or     optionally substituted indolyl, a prodrug, a pharmaceutically     acceptable salt or a solvate thereof, -   (4) a compound as described in (1) or (2), wherein R¹ is heteroaryl     which may be substituted with a group of the formula: -Z¹-Z² wherein     Z¹ is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO₂—,     —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO₂—, —CH₂—O—, —CH₂—NH—C(═O)—,     —CH₂—NH—C(═O)—O—, —CH₂—NH—SO₂— or —CH₂—C(═O)— and Z² is alkyl or     optionally substituted amino; carboxy; halogen; hydroxy; or nitro, a     prodrug, a pharmaceutically acceptable salt or a solvate thereof, -   (5) a compound as described in any one of (1) to (4), wherein R³ is     —CH₂—CH₂—CH₂——CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴,     —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; R⁴ is     hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically     acceptable salt or a solvate thereof, -   (6) a compound as described in (5), wherein R³ is     —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴; R⁴ is     hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically     acceptable salt or a solvate thereof, -   (7) a pharmaceutical composition containing a compound, a prodrug, a     pharmaceutically acceptable salt, or a solvate thereof as described     in any one of (1) to (6), -   (8) a pharmaceutical composition having an antagonistic activity     against PGD₂ receptor as described in (7), -   (9) a pharmaceutical composition as described in (7), which is used     for the treatment of nasal, -   (10) a pharmaceutical composition as described in (7), which is used     for the treatment of allergic conjunctivitis, -   (11) a pharmaceutical composition as described in (7), which is used     for the treatment of allergic rhinitis, -   (12) a method for treating nasal blockage, allergic conjunctivitis     or allergic rhinitis, which comprises administrating a composition     as described in (7), and -   (13) use of the compound as described in any one of (1) to (6) for     the preparation of a pharmaceutical composition for treating nasal     blockage, allergic conjunctivitis or allergic rhinitis.

The terms used herein is explained below. Each term used herein is defined to have meanings below in either case of a single or a joint use with other terms.

The term “heteroaryl” includes a 5- to 7-membered aromatic heterocycle containing one or more oxygen atom, sulfur atom and/or nitrogen atom in the ring, or such an aromatic heterocycle as fused with one or more carbocycle or other aromatic heterocycle, which has a bond at any substitutable. Any one of aromatic heterocycle and aromatic carbocycle may have a bond.

Examples of “heteroaryl” include pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazolyl (e.g., 3-pyrazolyl, 4pyrazolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), carbazolyl (e.g., 1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), furyl (e.g., 2-furyl, 3-furyl), benzofuryl (e.g., 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl, 7-benzofuryl), thienyl (e.g., 2-thienyl, 3-thienyl), benzothienyl (e.g., benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl), dibenzothienyl (e.g., 2-dibenzothienyl, 3-dibenzothienyl), dibenzofuryl (e.g., 2-dibenzofuryl, 3-dibenzofuryl), naphthothienyl (e.g., naphtho[2,3-b]thiophen-2-yl, naphtho[2,3-b]thiophen-3-yl, naphtho[1.2-b]thiophen-2-yl, naphtho[1.2-b]thiophen-3-yl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), imidazothiazolyl (e.g., imidazo[2.1-b]thiazol-2-yl, imidazo[2.1-b]thiazol-3-yl), benzoisoxazolyl (e.g., benzo[d]isoxazol-3-yl), benzothiazolyl (e.g., benzo[d]thiazol-2-yl), thienopyrrolyl (e.g., thieno[2,3-b]pyrrole-2-yl, thieno[2,3-b]pyrrole-3-yl, thieno[2,3-b]pyrrole-5-yl, thieno[2,3-c]pyrrole-2-yl, thieno[2,3-c]pyrrole-4-yl, thieno[3,2-b]pyrrole-2-yl, thieno[3,2-b]pyrrole-3-yl, thieno[3,2-b]pyrrole-5-yl), and the like.

Thienyl, benzothienyl, furyl, benzofuryl, pyrrolyl, are indolyl preferred.

The term of “aromatic carbocycle or other aromatic heterocycle” which may fuse the above “heteroaryl” includes 5- to 7-membered aromatic cycle which may contains one or more oxygen atom, sulfur atom and/or nitrogen atom in the ring, or such an aromatic ring as fused with one or more other aromatic rings.

The above “heteroaryl” may be fused 4- to 7-membered cycloalkane or 4- to 7-membered non-aromatic heterocycle. Examples of cycloalkane include cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Examples of non-aromatic heterocycle include pyrrolidine, piperazine, oxorane, 1,3-dioxorane, 1,4-dioxane, thiorane, or the like. The above “cycloalkane” and “non-aromatic heterocycle” may be fused with other aromatic carbocycle such as benzene or aromatic heterocycle such as thiophene or furan. Examples of heteroaryl fused with 4- to 7-membered cycloalkane or 4- to 7-membered non-aromatic heterocycle are illustrated below.

 

Examples of the substituent on “optionally substituted heteroaryl” include a group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO₂—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO₂—, —CH₂—O—, —CH₂—NH—C(═O)—, —CH₂—NH—C(═O)—O—, —CH₂—NH—SO₂—, or —CH₂—C(═O)—, and Z² is alkyl, haloalkyl, alkenyl, alkynyl, or optionally substituted amino; carboxy; halogen (F, Cl, Br, I); hydroxyalkyl; hydroxy; nitro; cyano; mercapto; thioformyl; thioacetyl; thiocarboxy; dithiocarboxy; thiocarbamoyl; sulfino; sulfo; sulfamoyl; sulfoamino and the like. A group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO₂—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO₂—, —CH₂—O—, —CH₂—NH—C(═O)—, —CH₂NH—C(═O)—O—, —CH₂—NH—SO₂—, or —CH₂—C(═O)—, and Z² is alkyl or optionally substituted amino; carboxy; halogen; hydroxy; and nitro are preferred. Further, A group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —NH—C(═O)—, or —C(═O)—, and Z² is alkyl or optionally substituted amino; halogen; and hydroxy are preferred. One to three of the above substituents may be at any suitable position on the above heteroaryl.

“Alkyl” includes a straight or branched C1 to C8 alkyl group or a C3 to C8 cycloalkyl group. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A straight or branched C1 to C3 alkyl group is preferred.

“Haloalkyl” includes the above alkyl substituted with one to three halogen(s). A straight or branched C1 to C3 haloalkyl is preferred. Trifluoromethyl, 2,2,2-trifluoroethyl and the like are exemplified.

“Alkenyl” includes the above alkyl having one to three double bond(s). A straight or branched C2 to C3 alkenyl is preferred. Vinyl, allyl, 1-propenyl, isopropenyl and the like are exemplified.

“Alkynyl” includes the above alkyl having one to three triple bond(s). A straight C2 to C3 alkynyl is preferred. Ethynyl and the like are preferred.

Examples of the substituent of “optionally substituted amino” include alkyl, alkyloxy, alkylsulfonyl, hydroxy, and the like. It may be mono- or di-substituted with these substituents.

“Hydroxy alkyl” includes the above alkyl substituted with one to three hydroxy. A straight or branched C1 to C3 hydroxyalkyl is preferred. Hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and the like are exemplified.

“Halogen” includes fluoro, chloro, bromo, and iodo.

A compound of the present invention has the following [2.2.1] and [3.1.1] bicyclic skeleton.

 

A compound of the present invention can be any of the following stereo isomers of [2.2.1] and [3.1.1] bicyclic skeleton.

In a case of

 

In a case of

 

In a case of

 

In these stereo isomers, preferable is a compound having the skeleton of the formula:

 

The present invention includes all stereo isomers of them and the optional mixtures thereof. Namely, the bond binding to the bicyclic ring is in R configuration or S configuration, and all of the stereo isomers (diastereomer, epimer, enantiomer and the like), racemates, and optional mixture thereof are included in the present invention.

Moreover, the α chain of the compound of the present invention can be in Z configuration or E configuration, thus a compound having any of the configurations and the mixture thereof are included in the present invention.

Further, as the α chain (R³) of the compound of the present invention, —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ and —CH₂—CH₂—CH₂—CH₂—COOR⁴ (R⁴ is hydrogen or alkyl; X¹ is —O— or —S—) are exemplified. Especially, —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ and —CH₂—CH₂—CH₂—CH₂—COOR⁴ (R⁴ is hydrogen; X¹ is —O— or —S—) are preferred. Further, —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴ and —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴ (R⁴ is hydrogen; X¹ is —O—or —S—) are preferred.

This invention includes not only a compound represented by the formula (I), but also a prodrug, a pharmaceutically acceptable salt or a solvate thereof.

A prodrug of a compound of the formula (I) is a derivative of the compound of the present invention having a group which can be decomposed chemically or metabolically, and such prodrug is converted to a pharmaceutically active compound of the present invention by means of solvolysis or by placing the compound in vivo under a physiological condition. Method for the selection and process of an appropriate prodrug derivative are described in the literature such as Design of Prodrugs, Elsevier, Amsterdam 1985.

When the compound of the formula (I) has a carboxyl group, an ester derivative prepared by reacting a basal acid compound with a suitable alcohol or an amide derivative prepared by reacting a basal acid compound with a suitable amine is exemplified as a prodrug. A particularly preferred ester derivative as an prodrug is an optionally substituted alkyl ester derivative (e.g., methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester), an arylalkyl ester derivative (e.g., benzyl ester, phenethyl ester, benzhydryl ester), or the like. A particularly preferred amide derivative as a prodrug is alkyl amide derivative (e.g., N-methyl amide, N-ethyl amide, N-(n-propyl)amide, N-isopropyl amide, N-(n-butyl)amide, N-isobutyl amide, N-(tert-butyl)amide), aryl alkyl amide (e.g., N-benzyl amide, N-phenethyl amide, benzhydryl amide), or the like.

When the compound of the formula (I) has a hydroxy group, an acyloxy derivative prepared by reacting with a suitable acyl halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred acyloxy derivative as a prodrug is a derivative substituted with optionally substituted alkylcarbonyloxy (e.g., —OCOC₂H₅, —OCO(tert-Bu), —OCOC₁₅H₃₁, —OCOCH₂CH₂COONa, —OCOCH(NH₂)CH₃, —OCOCH₂N(CH₃)₂—), optionally substituted arylcarbonyloxy (e.g., —OCO(m-COONa-Ph) or the like.

When the compound of the formula (I) has an amino group, an amide derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred amide derivative as a prodrug is a derivative substituted with optionally substituted alkylcarbonyl (e.g., —NHCO(CH₂)₂₀CH₃, —NHCOCH(NH₂)CH₃) or the like.

Examples of a salt of the compound of the formula (I) or its prodrug include alkali metal salts such as lithium salts, sodium salts or potassium salts, alkaline-earth metal salts such as calcium salts, salts with organic bases such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthylene methylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthorathene, 2-aminoanthorathene, dehydroabiethylamine, N-methylmorpholine, pyridine), basic amino acid salts such as arginine salts or lysine salts.

A solvate means a solvate with an organic solvent, a hydrate and the like of the compound of the formula (I), its prodrug or its pharmaceutically acceptable salt, for example, monohydrate, dihydrate or the like.

“A pharmaceutical composition having an antagonistic activity against PGD₂ receptor” means a pharmaceutical composition comprising at least one compound of the formula (I) having an antagonistic activity against a PGD₂ receptor. In addition to a compound of the formula (I), the other active agents (e.g. antiinflammatory agents, antiallergy agents and the like) and pharmaceutically acceptable admixtures (e.g., binding agent, filler and the like) may be included.

A PGD₂ antagonist is useful in the improvement of conditions due to excessive production of PGD₂, particularly as a composition for treating diseases in which mast cell dysfunction is involved, for example, systemic mastocytosis and disorder of systemic mast cell activation as well as for nasal blockage, allergic conjunctivitis, allergic rhinitis, airway contraction, asthma, urticaria, ischemic reperfusion injury, inflammation, and atopic dermatitis.

This invention includes a method for treating a condition due to excessive production of PGD₂ such as nasal blockage, allergic conjunctivitis, allergic rhinitis, and the like, which comprises administrating a compound represented by the formula (I). In addition, this invention includes use of the compound represented by the formula (I) for the preparation of a pharmaceutical composition for treating a condition due to excessive production of PGD₂ such as nasal blockage, allergic conjunctivitis or allergic rhinitis.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound represented by the formula (I) can be prepared in accordance with the following method.

 

-   R¹ is optionally substituted heteroaryl; -   R² is hydrogen or alkyl; -   R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴,     —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; -   R⁴ is hydrogen or alkyl; and -   X¹ is —O— or —S—.

As shown in the above process, the compound of the formula (I) can be prepared by reacting a carboxylic acid of the formula (M-2) or its reactive derivative with an amino compound of the formula (M-1).

The reactive derivatives of carboxylic acid of the formula (M-2) mean the corresponding acid halides (e.g., chloride, bromide, iodide), anhydrides (e.g., mixed anhydride with formic acid or acetic acid), active esters (e.g., N-hydroxysuccinimide ester), and the like, and include acylating agents used for the usual acylation of amino group.

For example, an acid halide is obtained by reacting the compound (M-2) with a thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride), and the like, in accordance with known methods as described in the literatures.

The reaction can be conducted under a condition generally used for the acylation of amino group. For example, in the case of condensation with the acid halide, the reaction is carried out in a solvent such as an ether solvent (e.g., diethyl ether, tetrahydrofuran, dioxane), benzene solvent (e.g., benzene, toluene, xylene), halogenated hydrocarbon solvent (e.g., dichloromethane, dichloroethane, chloroform) as well as ethyl acetate, dimethylformamide, dimethyl sulfoxide, acetonitrile, or the like, if necessary, in the presence of a base (e.g., organic base such as triethylamine, pyridine, N,N-dimethylaminopyridine, N-methylmorpholine; inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, or the like) under cooling, at room temperature, or under heating, preferably at a temperature ranging from −20° C. to ice-cooling temperature, or from room temperature to a refluxing temperature of the reaction system, during several min to several hr, preferably for 0.5 hr to 24 hr, more preferably for 1 hr to 12 hr.

When R⁴ is alkyl, a free form may be used without converting the carboxy group (M-2) into the reactive derivatives and the reaction may be conducted in the presence of a condensing agent (e.g., dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-methylaminopropyl)carbodiimide, N,N′-carbonyldiimidazole, or the like) usually used in the condensation reaction of amine and carboxylic acid.

When the substituent of “optionally substituted aryl” or “optionally substituted heteroaryl” of the compound of the formula (M-2) is substituted with a hydroxy group, an amino group or the like, such a compound can be used after protection by acetyl group or the like in accordance with the well known method.

In the reaction of the other reactive derivatives or free acid (M-2) with the amine (M-1), the reaction conditions are determined according to the property of each reactive derivative or free acid, in accordance with a known method. The reaction product can be purified in accordance with a conventional purification, such as the extraction with a solvent, chromatography, recrystallization, and the like.

  wherein Q is a protective group of an amino group; R², X¹ and R⁴ are as defined above.

The compounds represented by formula (M-1) can be prepared from the aldehyde derivative (Q is a protecting group such as benzyloxycarbonyl, t-butoxycarbonyl and the like) represented by a general formula (M-3a) or (M-3b) by one or more reaction(s) of a ylide compound under a Wittig reaction condition (Org. Reaction, 1965, 14, 270) in combination with other reactions.

For example, the aldehyde (M-3a) is reacted with phosphonium salt derived from 6-bromo-3-oxahexanoic acid described in WO97/40104 under a well known Wittig reaction condition to give a compound (M-4). The compound (M-4) is hydrogenated in the presence of palladium, platinum and the like to give a starting material (M-1a, X¹=O), wherein R³ is —CH₂CH₂CH₂CH₂OCH₂COOR⁴. Furthermore, after Wittig reaction using methoxymethyltriphenyl-phosphonium salt, followed by a hydrolysis with hydrochloric acid, formic acid, acetic acid and the like can furnish an aldehyde (M-3b). Under Wittig reaction condition using a stable ylide such as methyl (triphenylphophoranidene)acetate and the like or Honer-Emmons reaction condition using methyl dimethylphosphonoacetate, the above aldehyde can be converted into α,β-unsaturated carboxylic acid derivative represented by the formula (M-5). An alcohol derivative (M-6a, X¹=O) which is obtained by reduction of compound (M-5) is reacted with halogenated acetic acid or its ester derivative in accordance with well known methods to give a starting compound (M-1b, X¹=O) wherein R³ is —CH₂CH═CHCH₂OCH₂COOR⁴. Further, after an alcohol derivative (M-6a, X¹=O) is converted into a thiol derivative (X¹=S) in accordance with well known methods, the obtained compound is reacted with halogenated acetic acid derivative as shown the above to give a starting compound (M-1b, X¹=S) wherein R³ is —CH₂CH═CHCH₂SCH₂COOR⁴. Also, after an alcohol derivative (M-6a, X¹=O) is converted into a halogenated derivative in accordance with well known methods, the obtained compound is reacted with a glycolic acid or a thioglycollic acid in the presence of a base to give the above compound (M-1b, X¹=S). The double bonds in the R³ can be reduced by hydrogenation in the presence of catalyst such as palladium, platinum, and the like at the suitable stage to give a corresponding saturated derivative (M-1a, X¹=O or S) at ease.

The aldehyde (M-3b) is converted into a compound represented by the formula (M-7) by Wittig reaction using 2-(1,3-dioxolane-2-yl)ethyltriphenylphosphonium salt. A hydrogenation of the compound (M-7) and an acidic hydrolysis of acetal are carried out to give the aldehyde (M-3c) as shown in the above. Under Wittig reaction condition using a stable ylide such as methyl (triphenylphophoranidene)acetate and the like or Honer-Emmons reaction condition using methyl dimethylphosphonoacetate, the above aldehyde (M-3c) can be converted into a starting compound (M-1c) wherein R³ corresponds to —CH₂CH₂CH₂CH₂CH═CHCOOR⁴.

Amidation with a starting carboxylic acid (M-2) can be accomplished after a deprotection of an amino protecting group Q in a way of conversion to α-chain, if necessary.

In case of the introduction of a substituent(s) into the “optionally substituted aryl” or “optionally substituted heteroaryl”, the change of the functional group can be performed before or after reacting a carboxylic acid or its reactive derivative thereof (M-2) with the amine (M-1). For example, the compound having an aromatic heterocycle substituted with a nitro group can be prepared through the nitration of the compound with a nitrating acid. Moreover, the compound having an aromatic heterocycle substituted with an amino group can be prepared through the reduction of the above-obtained compound with tin in the presence of hydrochloride. Moreover, the compound having an aromatic heterocycle substituted with a hydroxy group can be prepared through the diazonization of the above-obtained compound and the hydrolysis with alkali. On the other hand, the compound having an aromatic heterocycle substituted with an alkoxy group can be prepared through the reaction of the diazonium derivative with alcohol. The compound having an aromatic heterocycle substituted with halogen can be prepared through Sandmeyer reaction, the reaction of the diazonium derivative with a copper salt (e.g., CuCl₂, CuBr₂). The compound having an aromatic heterocycle substituted with halogen can be also prepared through the direct reaction of the compound having an aromatic heterocycle with chlorine and the like. Using the above-mentioned methods appropriately, halogen can be introduced into a desired position(s). The group of alkyl, alkenyl or acyl group can be directly introduced into an aromatic heterocycle through Friedel Crafts reaction with alkylating agent, an alkenylating agent, or an acylating agent, respectively, in the presence of anhydrous aluminum chloride and the like.

When using the compound (I) of the present invention in treatment, it can be formulated into ordinary formulations for oral and parenteral administration. A pharmaceutical composition containing the compound (I) of the present invention can be in the form for oral and parenteral administration. Specifically, it can be formulated into formulations for oral administration such as tablets, capsules, granules, powders, syrup, and the like; or those for parenteral administration such as injectable solution or suspension for intravenous, intramuscular, or subcutaneous injection, inhalant, eye drops, nasal drops, suppositories, or percutaneous formulations such as ointment.

In preparing the formulations, carriers, excipients, solvents, and bases known to one having ordinary skill in the art may be used. In case of tablets, they are prepared by compressing or formulating an active ingredient together with auxiliary components. Examples of usable auxiliary components include pharmaceutically acceptable excipients such as binders (e.g., cornstarch), fillers (e.g., lactose, microcrystalline cellulose), disintegrants (e.g., starch sodium glycolate) or lubricants (e.g., magnesium stearate). Tablets may be coated appropriately. In case of liquid formulations such as syrups, solutions, or suspensions, they may contain suspending agents (e.g., methyl cellulose), emulsifiers (e.g., lecithin), preservatives, and the like. In case of injectable formulations, it may be in the form of solution, suspension, or oily or aqueous emulsion, which may contain suspension-stabilizing agents or dispersing agent, and the like. In case of an inhalant, it is formulated into a liquid formulation applicable to an inhaler. In case of eye drops, it is formulated into a solution or a suspension.

Especially, in case of a nasal drug for treating nasal blockage, it can be used as a solution or suspension prepared by a conventional formulating method, or administered as a powder formulated using a powdering agent (e.g., hydroxypropyl cellulose, carbopole) into the nasal cavity. Alternatively, it can be used as an aerosol filled into a special container together with a solvent of low boiling point.

In a case using as an eyewash drug for treating allergic conjunctivitis, it can be used as a solution or suspension of the compound or can be used by solving or suspending the compound before use. A stabilizing agent, solubilizing agent, suspending agent, emulsifier, buffer, preservatives and the like can be included. In a case using as an eyewash drug, aseptic treatment is preferable.

Although an appropriate dosage of the compound (I) varies depending on the administration route, age, body weight, sex, or conditions of the patient, and the kind of drug(s) used together, if any, and should be determined by the physician in the end, in the case of oral administration, the daily dosage can generally be between 0.01-100 mg, preferably 0.01-10 mg, more preferably 0.01-1 mg, per kg body weight. In case of parenteral administration, the daily dosage can generally be between 0.001-100 mg, preferably 0.001-1 mg, more preferably 0.001-0.1 mg, per kg body weight. The daily dosage can be administered in 1-4 divisions.

EXAMPLE

The following examples are provided to further illustrate the present invention and are not to be construed as limiting the scope.

Example 1 Preparation of (Ic-4)

 

Process 1

To a solution of compound (1) (10.11 g, 39.9 mmol) in toluene (100 ml) was added triphenylphosphoranylidene acetic acid methyl ester (14.68 g, 43.9 mmol) and the resulting mixture was stirred for 17 h at room temperature. Hexane (100 ml) was added to the mixture and the insoluble residue was filtered off. The filtration was concentrated to give 16.56 g of residue. 16.12 g of the residue was dissolved in THF(160 ml), 2N lithium hydroxide aq. (40 ml) was added to the solution and the resulting mixture was stirred for 5 h at 60° C. After THF was concentrated in vacuo, the residue was diluted with water (100 ml). The water layer was washed with toluene twice and acidified with hydrochloric acid (pH=1) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, and concentrated. To a solution of the residue in methanol was added 10% palladium-carbon (360 mg) and the resulting mixture was stirred for 3 h under hydrogen atmosphere. The reaction mixture was filtered and concentrated and the residues was dissolved in THF (120 ml). To the mixture were added triethylamine (6.2 ml, 44.5 mmol) and ethyl chloroformate (4.3 ml, 44.5 mmol ) at ice-cooling, and the resulting mixture was stirred for 30 min at ice-cooling. The insoluble salt was filtered off and sodium borohydride (3.06 g, 80.9 mmol) was added to the filtration. To the mixture was added methanol (40 ml) dropwise over 30 min and the mixture was stirred for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine respectively and dried. The residue was crystallized from hexane-ethyl acetate (90:10) to give compound (2) (8.77 g; yield 80%). mp. 90-92° C.

Process 2

To a solution of the compound (2) (1.68 g, 5.94 mmol) in toluene (17 ml) were added t-butyl bromoacetate (1.32 ml, 68.91 mmol), sodium hydrogensulfate (201 mg, 0.6 mmol) and 50% sodium hydroxide aq. (1.7 ml) and the resulting mixture was vigorously stirred for 22 h at room temperature. Toluene layer was separated, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=7:1) to give compound (3) (1.60 g; yield 68%).

Process 3

To a solution of the compound (3) (10.42 g, 26.2 mmol) in methanol (50 ml) was added 4N dioxane solution of hydrogen chloride (65.5 ml, 262 mmol) and the resulting mixture was stirred for 5 h at room temperature. The reaction mixture was concentrated in vacuo to give crystalline residue. The residue was washed with hexane-ether to give compound (4) (6.88 g; yield 90%).

Process 4

To a solution of compound (4) (642 mg, 2.20 mmol) in THF (8 ml) were added thiophene-3-carboxylic acid (256 mg, 2.00 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol) and triethylamine (0.34 ml, 2.40 mmol) at ice-cooling. Further, 3-ethyl-3-(3-dimethylaminopropyl)carbodiimide (370 mg, 2.40 mmol) was added to the mixture at ice-cooling. The reaction mixture was stirred for 16 h at room temperature and diluted with ethyl acetate. The resulting mixture was washed with dilute hydrochloric acid and sodium hydrogencarbonate respectively, dried, concentrated, and chromatographed on silica gel (toluene-hexane=3:1) to give compound (5) (627 mg; yield 86%). m.p. 68-70° C.

Process 5

To a solution of compound (5) (620 mg, 1.70 mmol) in methanol (2 ml)-THF (1 ml) was added 4N sodium hydroxide aq.(1.0 ml, 4.0 mmol) and the resulting mixture was stirred for 16 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid. and extracted with ethyl acetate. The organic layer was washed with water and brine respectively, dried and concentrated. The residue was crystallized from methanol-water (5:7) to give compound (Ic-4) (461 mg; yield 77%). m.p. 104-105° C.

Example 2 Preparation of Compound (Ie-34)

 

Process 1

To a solution of compound (2) (2.28 g, 8.05 mmol) in dichloromethane (20 ml) were added triphenylphosphine (2.32 g, 8.85 mmol) and N-bromosuccinimide (1.58 g, 8.85 mmol) at ice-cooling and the resulting mixture was stirred for 1 h at the same temperature. The reaction mixture was diluted with toluene, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=9:1) to give compound (6) (2.70 g; yield 97%).

Process 2

To a solution of sodium methoxide (842 mg, 15.6 mmol) in methanol (20 ml) was added methyl thioglycolate (1.40 ml, 15.6 mmol) and the resulting mixture was stirred for 15 min at room temperature. To the mixture was added a THF (20 ml) solution of compound (6) (2.70 g, 7.80 mmol) and the resulting mixture was stirred for 15 h. The reaction was diluted with ethyl acetate, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=78:22) to give compound (7) (2.84 g; yield 98%).

Process 3

4N Ethyl acetate solution of hydrogen chloride (15 ml) was added to compound (7) (2.84 g, 7.64 mmol) and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated in vacuo to give the residue. The residue was crystallized from hexane-ether to give compound (8) (2.16 g; yield 92%).

Process 4

To a solution of compound (8) (246 mg, 0.80 mmol) in THF (6 ml) were added benzothiophene-7-carboxylic acid (150 mg, 0.80 mmol), 1-hydroxybenzotriazole (11 mg, 0.08 mmol), triethylamine (0.12 ml, 0.96 mmol) at ice-cooling. Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (149 mg, 0.96 mmol) was added to the mixture at ice-cooling. The reaction mixture was stirred for 16 h at room temperature and diluted with ethyl acetate. The resulting mixture was washed with dilute hydrochloric acid and sodium hydrogencarbonate aq. respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=3:1) to give compound (9) (324 mg; yield 94%).

Process 5

To a solution of compound (9) (315 mg, 0.73 mmol) in THF (3.6 ml)-methanol (7.3 ml) was added 1N sodium hydroxide aq.(1.82 ml, 1.82 mmol) and the resulting mixture was stirred for 48 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine respectively to give compound (Ie-34) (301 mg; yield 99%).

Example 3 Preparation of Compound (IIb-28)

 

Process 1

A solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (3.0 ml, 14.3 mmol) and 18-crown-6 (5.64 g, 21.3 mmol) in THF (100 ml) was cooled at −55° C. and bis(trimethylsilyl)amide potassium (0.5M toluene solution, 28.5 ml, 14.3 mmol) was added dropwise to the mixture. The resulting mixture was stirred for 15 min. To the mixture was added a solution of compound (10) (2.0 g, 7.11 mmol) in THF (20 ml) was added dropwise over 15 min and the mixture was stirred for 1 h at the same temperature. The reaction mixture was allowed to warm to 0° C., diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=4:1) to give compound (11) (2.16 g; yield 90%).

Process 2

A solution of compound (11) (1.37 g, 4.05 mmol) in dichloromethane (10 ml)-hexane (10 ml) was cooled to −60° C. and diisopropylaluminum hydride (0.95M hexane solution, 10.7 ml, 10.2 mmol) was added dropwise to the solution. The mixture was stirred for 30 min at the same temperature and methanol (0.6 ml) was added. The resulting mixture was allowed to warm to room temperature and 2N hydrochloric acid was added. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium hydrogencarbonate aq. and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=2:1) to give compound (12) (1.14 g; yield 91%). m.p. 67-69° C.

Process 3

To a solution of compound (12) (1.03 g, 3.31 mmol) in toluene (10 ml) were added t-butyl bromoacetate (0.70 ml, 4.30 mmol), tetrabutylammonium hydrogensulfate (170 mg, 0.5 mmol), and 50% sodium hydroxide (1.5 ml) and the resulting mixture was vigorously stirred for 18 h at room temperature. The reaction mixture was extracted with toluene, washed with water and brine respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=4:1) to give compound (13) (1.32 g; yield 94%).

Process 4

To a solution of compound (13) (1.3 g, 3.07 mmol) in toluene (3 ml) was added trifluoroacetic acid (3.5 ml, 46 mmol) and the resulting mixture was stirred for 3.5 h at 65° C. The reaction mixture was concentrated in vacuo and methanol (30 ml) and concentrated sulphuric acid (0.33 ml) were added to the mixture. The resulting mixture was stirred for 1 h at reflux. The reaction mixture was concentrated and the residue was dissolved in toluene. To the mixture was added triethylamine (4.3 ml, 30 mmol) and sodium hydrogencarbonate aq. respectively. The toluene layer was separated, washed with water and brine respectively, dried, and concentrated to give compound (14) (697 mg; yield 81%).

Process 5

To a solution of compound (14) (141 mg, 0.50 mmol) in THF (4 ml) were added 5-fluorobenzothiophene-3-carboxylic acid (98 mg, 0.50 mmol) and 1-hydroxybenzotriazole (7 mg, 0.05 mmol) at ice-cooling. Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (93 mg, 0.6 mmol) was added at the same temperature. The reaction mixture was stirred for 16 h at room temperature, diluted with ethyl acetate, washed with dilute hydrochloric acid and sodium hydrogencarbonate aq. respectively, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=83:17) to give compound (15) (93 mg; yield 40%).

Process 6

To a solution of compound (15) (93 mg, 0.20 mmol) in THF (1 ml)-methanol (2 ml) was added 1N sodium hydroxide aq.(0.5 ml, 0.5 mmol) and the resulting mixture was stirred for 18 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine respectively to give compound (IIb-28) (82 mg; yield 91%).

Example 4 Preparation of Compound (IIa-52)

 

Process 1

A suspension of 2-(1,3-dioxorane-2-yl)ethyltriphenylphosphonium bromide (13.28 g, 30.0 mmol) in THF (60 ml) was cooled to −30° C. and potassium t-butoxide (6.73 g, 60.0 mmol) was added. The mixture was stirred for 1 h at −30° C. to 0° C. and allowed to cool to −25° C. To the mixture was added a solution of compound (10) (5.62 g, 20.0 mmol) in THF (40 ml) dropwise over 15 min. The reaction mixture was allowed to warm to 0° C., stirred for additional 1.5 h, diluted with water. The water layer was extracted with ethyl acetate and the extract is washed with water and brine, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=85:15) to give compound (16) (6.27 g; yield 86%).

Process 2

A solution of compound (16) (4.10 g, 11.2 mmol) in methanol (41 ml) was stirred for 2 h in the presence of 10% palladium-carbon (0.21 g) under hydrogen atmosphere. The reaction mixture was filtered and concentrated to give a residue (4.12 g; yield 100%). To a solution of the crude compound (3.68 g, 10.0 mmol) in acetone-water (4:1, 50 ml) was added pyridinium p-toluenesulfonate (503 mg, 2.0 mmol) and the mixture was heated for 6 h at reflux. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, concentrated. A solution of the residue in toluene (35 ml) was added methyl (triphenylphosphoranylidene)acetate (2.93 g, 8.76 mmol) and the resulting mixture was stirred for 18 h at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried, concentrated, and chromatographed on silica gel (hexane-ethyl acetate=85:15) to give compound (17) (2.71 g; yield 71%).

Process 3

To a solution of compound (17) (2.35 g, 6.19 mmol) in dichloromethane (38 ml) was added trifluoroacetic acid (3.82 ml, 49.5 mmol) and the resulting mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in toluene (50 ml) and water (10 ml). The water layer was alkalinized with 2N sodium hydroxide (pH=10). Toluene layer was separated, washed with water and brine, dried, and concentrated to give compound (18) (1.70 g, yield 98%).

Process 4

To a solution of compound (18) (280 mg, 1.0 mmol) in THF (5 ml) were added 5-acetoxybenzofuran-3-carboxylic acid (220 mg, 1.0 mmol), 1-hydroxybenzotriazole (13 mg, 0.1 mmol). Further, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (200 mg, 1.3 mmol) was added at ice-cooling. After the reaction mixture was stirred for 16 h at room temperature, the mixture was diluted with toluene, washed with dilute hydrochloric acid and sodium hydrogencarbonate aq. respectively, dried, and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate=3:1) to give compound (19) (422 mg; yield 88%). m.p. 119-120° C.

Process 5

To a solution of compound (19) (422 mg, 0.88 mmol) in THF (5.6 ml) was added 1N lithium hydroxide aq. (3.0 ml, 3.0 mmol) and the resulting mixture was stirred for 20 h at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine respectively, dried, and concentrated. The residue was crystallized from hexane-ethyl acetate to give compound (IIa-52) (327 mg; yield 87%). m.p. 159-160° C.

The structure and physical property of the compound prepared in accordance with the above examples are shown below. Each sign such as Ia, Ib, IIe, and IIf used in the following Tables means the partial structure represented below:

 

TABLE 1

R¹ Ia Ib Ic Id Ie If

Ia-1 Ib-1 Ic-1 Id-1 Ie-1 If-1

Ia-2 Ib-2 Ic-2 Id-2 Ie-2 If-2

Ia-3 Ib-3 Ic-3 Id-3 Ie-3 If-3

Ia-4 Ib-4 Ic-4 Id-4 Ie-4 If-4

Ia-5 Ia-5 Ic-5 Id-5 Ie-5 If-5

Ia-6 Ib-6 Ic-6 Id-6 Ie-6 If-6

Ia-7 Ib-7 Ic-7 Id-7 Ie-7 If-7

Ia-8 Ib-8 Ic-8 Id-8 Ie-8 If-8

Ia-9 Ib-9 Ic-9 Id-9 Ie-9 If-9

Ia-10 Ib-10 Ic-10 Id-10 Ie-10 If-10  

TABLE 2

R¹ Ia Ib Ic Id Ie If

Ia- 11 Ib-11 Ic-11 Id-11 Ie-11 If-11

Ia- 12 Ib-12 Ic-12 Id-12 Ie-12 If-12

Ia- 13 Ib-13 Ic-13 Id-13 Ie-13 If-13

Ia- 14 Ib-14 Ic-14 Id-14 Ie-14 If-14

Ia- 15 Ia-15 Ic-15 Id-15 Ie-15 If-15

Ia- 16 Ib-16 Ic-16 Id-16 Ie-16 If-16

Ia- 17 Ib-17 Ic-17 Id-17 Ie-17 If-17

Ia- 18 Ib-18 Ic-18 Id-18 Ie-18 If-18

Ia- 19 Ib-19 Ic-19 Id-19 Ie-19 If-19

Ia- 20 Ib-20 Ic-20 Id-20 Ie-20 Ief-20  

TABLE 3

R¹ Ia Ib Ic Id Ie If

Ia- 21 Ib-21 Ic-21 Id-21 Ie-21 If-21

Ia- 22 Ib-22 Ic-22 Id-22 Ie-22 If-22

Ia- 23 Ib-23 Ic-23 Id-23 Ie-23 If-23

Ia- 24 Ib-24 Ic-24 Id-24 Ie-24 If-24

Ia- 25 Ia-25 Ic-25 Id-25 Ie-25 If-25

Ia- 26 Ib-26 Ic-26 Id-26 Ie-26 If-26

Ia- 27 Ib-27 Ic-27 Id-27 Ie-27 If-27

Ia- 28 Ib-28 Ic-28 Id-28 Ie-28 If-28

Ia- 29 Ib-29 Ic-29 Id-29 Ie-29 If-29

Ia- 30 Ib-30 Ic-30 Id-30 Ie-30 If-30  

TABLE 4

R¹ Ia Ib Ic Id Ie If

Ia-31 Ib-31 Ic-31 Id-31 Ie-31 If-31

Ia-32 Ib-32 Ic-32 Id-32 Ie-32 If-32

Ia-33 Ib-33 Ic-33 Id-33 Ie-33 If-33

Ia-34 Ib-34 Ic-34 Id-34 Ie-34 If-34

Ia-35 Ia-35 Ic-35 Id-35 Ie-35 If-35

Ia-36 Ib-36 Ic-36 Id-36 Ie-36 If-36

Ia-37 Ib-37 Ic-37 Id-37 Ie-37 If-37

Ia-38 Ib-38 Ic-38 Id-38 Ie-38 If-38

Ia-39 Ib-39 Ic-39 Id-39 Ie-39 If-39

Ia-40 Ib-40 Ic-40 Id-40 Ie-40 If-40  

TABLE 5

R¹ Ia Ib Ic Id Ie If

Ia- 41 Ib-41 Ic-41 Id-41 Ie-41 If-41

Ia- 42 Ib-42 Ic-42 Id-42 Ie-42 If-42

Ia- 43 Ib-43 Ic-43 Id-43 Ie-43 If-43

Ia- 44 Ib-44 Ic-44 Id-44 Ie-44 If-44

Ia- 45 Ia-45 Ic-45 Id-45 Ie-45 If-45

Ia- 46 Ib-46 Ic-46 Id-46 Ie-46 If-46

Ia- 47 Ib-47 Ic-47 Id-47 Ie-47 If-47

Ia- 48 Ib-48 Ic-48 Id-48 Ie-48 If-48

Ia- 49 Ib-49 Ic-49 Id-49 Ie-49 If-49

Ia- 50 Ib-50 Ic-50 Id-50 Ie-50 If-50  

TABLE 6

R¹ Ia Ib Ic Id Ie If

Ia- 51 Ib-51 Ic-51 Id-51 Ie-51 If-51

Ia- 52 Ib-52 Ic-52 Id-52 Ie-52 If-52

Ia- 53 Ib-53 Ic-53 Id-53 Ie-53 If-53

Ia- 54 Ib-54 Ic-54 Id-54 Ie-54 If-54

Ia- 55 Ia-55 Ic-55 Id-55 Ie-55 If-55

Ia- 56 Ib-56 Ic-56 Id-56 Ie-56 If-56

Ia- 57 Ib-57 Ic-57 Id-57 Ie-57 If-57

Ia- 58 Ib-58 Ic-58 Id-58 Ie-58 If-58

Ia- 59 Ib-59 Ic-59 Id-59 Ie-59 If-59

Ia- 60 Ib-60 Ic-60 Id-60 Ie-60 If-60  

TABLE 7

R¹ Ia Ib Ic Id Ie If

Ia-61 Ib-61 Ic-61 Id-61 Ie-61 If-61

Ia-62 Ib-62 Ic-62 Id-62 Ie-62 If-62

Ia-63 Ib-63 Ic-63 Id-63 Ie-63 If-63

Ia-64 Ib-64 Ic-64 Id-64 Ie-64 If-64

Ia-65 Ia-65 Ic-65 Id-65 Ie-65 If-65

Ia-66 Ib-66 Ic-66 Id-66 Ie-66 If-66

Ia-67 Ib-67 Ic-67 Id-67 Ie-67 If-67

Ia-68 Ib-68 Ic-68 Id-68 Ie-68 If-68

Ia-69 Ib-69 Ic-69 Id-69 Ie-69 If-69

Ia-70 Ib-70 Ic-70 Id-70 Ie-70 If-70  

TABLE 8

R¹ Ia Ib Ic Id Ie If

Ia- 71 Ib-71 Ic-71 Id-71 Ie-71 If-71

Ia- 72 Ib-72 Ic-72 Id-72 Ie-72 If-72

Ia- 73 Ib-73 Ic-73 Id-73 Ie-73 If-73

Ia- 74 Ib-74 Ic-74 Id-74 Ie-74 If-74

Ia- 75 Ia-75 Ic-75 Id-75 Ie-75 If-75

Ia- 76 Ib-76 Ic-76 Id-76 Ie-76 If-76

Ia- 77 Ib-77 Ic-77 Id-77 Ie-77 If-77

Ia- 78 Ib-78 Ic-78 Id-78 Ie-78 If-78

Ia- 79 Ib-79 Ic-79 Id-79 Ie-79 If-79

Ia- 80 Ib-80 Ic-80 Id-80 Ie-80 If-80  

TABLE 9

R¹ Ia Ib Ic Id Ie If

Ia- 81 Ib- 81 Ic- 81 Id- 81 Ie- 81 If-81

Ia- 82 Ib- 82 Ic- 82 Id- 82 Ie- 82 If-82

Ia- 83 Ib- 83 Ic- 83 Id- 83 Ie- 83 If-83

Ia- 84 Ib- 84 Ic- 84 Id- 84 Ie- 84 If-84

Ia- 85 Ib- 85 Ic- 85 Id- 85 Ie- 85 If-85

Ia- 86 Ib- 86 Ic- 86 Id- 86 Ie- 86 If-86

Ia- 87 Ib- 87 Ic- 87 Id- 87 Ie- 87 If-87

Ia- 88 Ib- 88 Ic- 88 Id- 88 Ie- 88 If-88

Ia- 89 Ib- 89 Ic- 89 Id- 89 Ie- 89 If-89

Ia- 90 Ib- 90 Ic -90 Id- 90 Ie- 90 If-90  

TABLE 10

R¹ Ia Ib Ic Id Ie If

Ia-91 Ib-91 Ic-91 Id-91 Ie-91 If-91

Ia-92 Ib-92 Ic-92 Id-92 Ie-92 If-92

Ia-93 Ib-93 Ic-93 Id-93 Ie-93 If-93

Ia-94 Ib-94 Ic-94 Id-94 Ie-94 If-94

Ia-95 Ib-95 Ic-95 Id-95 Ie-95 If-95

Ia-96 Ib-96 Ic-96 Id-96 Ie-96 If-96

Ia-97 Ib-97 Ic-97 Id-97 Ie-97 If-97

Ia-98 Ib-98 Ic-98 Id-98 Ie-98 If-98

Ia-99 Ib-99 Ic-99 Id-99 Ie-99 If-99

Ia-100 Ib-100 Ic-100 Id-100 Ie-100 If-100  

TABLE 11

R¹ Ia Ib Ic Id Ie If

Ia-101 Ib-101 Ic-101 Id-101 Ie-101 If-101

Ia-102 Ib-102 Ic-102 Id-102 Ie-102 If-102

Ia-103 Ib-103 Ic-103 Id-103 Ie-103 If-103

Ia-104 Ib-104 Ic-104 Id-104 Ie-104 If-104

Ia-105 Ib-105 Ic-105 Id-105 Ie-105 If-105

Ia-106 Ib-106 Ic-106 Id-106 Ie-106 If-106

Ia-107 Ib-107 Ic-107 Id-107 Ie-107 If-107

Ia-108 Ib-108 Ic-108 Id-108 Ie-108 If-108

Ia-109 Ib-109 Ic-109 Id-109 Ie-109 If-109

Ia-110 Ib-110 Ic-110 Id-110 Ie-110 If-110  

TABLE 12

R¹ Ia Ib Ic Id Ie If

Ia-111 Ib-111 Ic-111 Id-111 Ie-111 If-111

Ia-112 Ib-112 Ic-112 Id-112 Ie-112 If-112

Ia-113 Ib-113 Ic-113 Id-113 Ie-113 If-113

Ia-114 Ib-114 Ic-114 Id-114 Ie-114 If-114

Ia-115 Ib-115 Ic-115 Id-115 Ie-115 If-115

Ia-116 Ib-116 Ic-116 Id-116 Ie-116 If-116

Ia-117 Ib-117 Ic-117 Id-117 Ie-117 If-117

Ia-118 Ib-118 Ic-118 Id-118 Ie-118 If-118

Ia-119 Ib-119 Ic-119 Id-119 Ie-119 If-119

Ia-120 Ib-120 Ic-120 Id-120 Ie-120 If-120  

TABLE 13

R¹ Ia Ib Ic Id Ie If

Ia-121 Ib-121 Ic-121 Id-121 Ie-121 If-121

Ia-122 Ib-122 Ic-122 Id-122 Ie-122 If-122

Ia-123 Ib-123 Ic-123 Id-123 Ie-123 If-123

Ia-124 Ib-124 Ic-124 Id-124 Ie-124 If-124

Ia-125 Ib-125 Ic-125 Id-125 Ie-125 If-125

Ia-126 Ib-126 Ic-126 Id-126 Ie-126 If-126

Ia-127 Ib-127 Ic-127 Id-127 Ie-127 If-127

Ia-128 Ib-128 Ic-128 Id-128 Ie-128 If-128

Ia-129 Ib-129 Ic-129 Id-129 Ie-129 If-129

Ia-130 Ib-130 Ic-130 Id-130 Ie-130 If-130  

TABLE 14

R¹ Ia Ib Ic Id Ie If

Ia-131 I-131b Ic-131 Id-131 Ie-131 If-131

Ia-132 I-132b Ic-132 Id-132 Ie-132 If-132

Ia-133 I-133b Ic-133 Id-133 Ie-133 If-133

Ia-134 I-134b Ic-134 Id-134 Ie-134 If-134

Ia-135 I-135b Ic-135 Id-135 Ie-135 If-135

Ia-136 I-136b Ic-136 Id-136 Ie-136 If-136

Ia-137 I-137b Ic-137 Id-137 Ie-137 If-137

Ia-138 I-138b Ic-138 Id-138 Ie-138 If-138

Ia-139 I-139b Ic-139 Id-139 Ie-139 If-139

Ia-140 I-140b Ic-140 Id-140 Ie-140 If-140  

TABLE 15

R¹ Ia Ib Ic Id Ie If

Ia-141 Ib-141 Ic-141 Id-141 Ie-141 If-141

Ia-142 Ib-142 Ic-142 Id-142 Ie-142 If-142

Ia-143 Ib-143 Ic-143 Id-143 Ie-143 If-143

Ia-144 Ib-144 Ic-144 Id-144 Ie-144 If-144

Ia-145 Ib-145 Ic-145 Id-145 Ie-145 If-145

Ia-146 Ib-146 Ic-146 Id-146 Ie-146 If-146

Ia-147 Ib-147 Ic-147 Id-147 Ie-147 If-147

Ia-148 Ib-148 Ic-148 Id-148 Ie-148 If-148

Ia-149 Ib-149 Ic-149 Id-149 Ie-149 If-149

Ia-150 Ib-150 Ic-150 Id-150 Ie-150 If-150  

TABLE 16

R¹ Ia Ib Ic Id Ie If

Ia-151 Ib-151 Ic-151 Id-151 Ie-151 If-151

Ia-152 Ib-152 Ic-152 Id-152 Ie-152 If-152

Ia-153 Ib-153 Ic-153 Id-153 Ie-153 If-153

Ia-154 Ib-154 Ic-154 Id-154 Ie-154 If-154

Ia-155 Ib-155 Ic-155 Id-155 Ie-155 If-155

Ia-156 Ib-156 Ic-156 Id-156 Ie-156 If-156

Ia-157 Ib-157 Ic-157 Id-157 Ie-157 If-157

Ia-158 Ib-158 Ic-158 Id-158 Ie-158 If-158

Ia-159 Ib-159 Ic-159 Id-159 Ie-159 If-159

Ia-160 Ib-160 Ic-160 Id-160 Ie-160 If-160  

TABLE 17

R¹ Ia Ib Ic Id Ic If

Ia-161 Ib-161 Ic-161 Id-161 Ic-161 If-161

Ia-162 Ib-162 Ic-162 Id-162 Ic-162 If-162

Ia-163 Ib-163 Ic-163 Id-163 Ic-163 If-163

Ia-164 Ib-164 Ic-164 Id-164 Ic-164 If-164

Ia-165 Ib-165 Ic-165 Id-165 Ic-165 If-165

Ia-166 Ib-166 Ic-166 Id-166 Ic-166 If-166  

TABLE 18

R¹ IIa IIb IIc IId IIe IIf

IIa-1 IIb-1 IIc-1 IId-1 IIe-1 IIf-1

IIa-2 IIb-2 IIc-2 IId-2 IIe-2 IIf-2

IIa-3 IIb-3 IIc-3 IId-3 IIe-3 IIf-3

IIa-4 IIb-4 IIc-4 IId-4 IIe-4 IIf-4

IIa-5 IIb-5 IIc-5 IId-5 IIe-5 IIf-5

IIa-6 IIb-6 IIc-6 IId-6 IIe-6 IIf-6

IIa-7 IIb-7 IIc-7 IId-7 IIe-7 IIf-7

IIa-8 IIb-8 IIc-8 IId-8 IIe-8 IIf-8

IIa-9 IIb-9 IIc-9 IId-9 IIe-9 IIf-9

IIa- 10 IIb- 10 IIc- 10 IId- 10 IIe- 10 IIf- 10  

TABLE 19

R¹ IIa IIb IIc IId IIe IIf

IIa-11 IIb-11 IIc-11 IId-11 IIe-11 IIf-11

IIa-12 IIb-12 IIc-12 IId-12 IIe-12 IIf-12

IIa-13 IIb-13 IIc-13 IId-13 IIe-13 IIf-13

IIa-14 IIb-14 IIc-14 IId-14 IIe-14 IIf-14

IIa-15 IIb-15 IIc-15 IId-15 IIe-15 IIf-15

IIa-16 IIb-16 IIc-16 IId-16 IIe-16 IIf-16

IIa-17 IIb-17 IIc-17 IId-17 IIe-17 IIf-17

IIa-18 IIb-18 IIc-18 IId-18 IIe-18 IIf-18

IIa-19 IIb-19 IIc-19 IId-19 IIe-19 IIf-19

IIa-20 IIb-20 IIc-20 IId-20 IIe-20 IIf-20  

TABLE 20

R¹ IIa IIb IIc IId IIe IIf

IIa-21 IIb-21 IIc-21 IId-21 IIe-21 IIf-21

IIa-22 IIb-22 IIc-22 IId-22 IIe-22 IIf-22

IIa-23 IIb-23 IIc-23 IId-23 IIe-23 IIf-23

IIa-24 IIb-24 IIc-24 IId-24 IIe-24 IIf-24

IIa-25 IIb-25 IIc-25 IId-25 IIe-25 IIf-25

IIa-26 IIb-26 IIc-26 IId-26 IIe-26 IIf-26

IIa-27 IIb-27 IIc-27 IId-27 IIe-27 IIf-27

IIa-28 IIb-28 IIc-28 IId-28 IIe-28 IIf-28

IIa-29 IIb-29 IIc-29 IId-29 IIe-29 IIf-29

IIa-30 IIb-30 IIc-30 IId-30 IIe-30 IIf-30  

TABLE 21

R¹ IIA IIb IIc IId IIe IIf

IIa-31 IIb-31 IIc-31 IId-31 IIe-31 IIf-31

IIa-32 IIb-32 IIc-32 IId-32 IIe-32 IIf-32

IIa-33 IIb-33 IIc-33 IId-33 IIe-33 IIf-33

IIa-34 IIb-34 IIc-34 IId-34 IIe-34 IIf-34

IIa-35 IIb-35 IIc-35 IId-35 IIe-35 IIf-35

IIa-36 IIb-36 IIc-36 IId-36 IIe-36 IIf-36

IIa-37 IIb-37 IIc-37 IId-37 IIe-37 IIf-37

IIa-38 IIb-38 IIc-38 IId-38 IIe-38 IIf-38

IIa-39 IIb-39 IIc-39 IId-39 IIe-39 IIf-39

IIa-40 IIb-40 IIc-40 IId-40 IIe-40 IIf-40  

TABLE 22

R¹ IIa IIb IIc IId IIe IIf

IIa-41 IIb-41 IIc-41 IId-41 IIe-41 IIf-41

IIa-42 IIb-42 IIc-42 IId-42 IIe-42 IIf-42

IIa-43 IIb-43 IIc-43 IId-43 IIe-43 IIf-43

IIa-44 IIb-44 IIc-44 IId-44 IIe-44 IIf-44

IIa-45 IIb-45 IIc-45 IId-45 IIe-45 IIf-45

IIa-46 IIb-46 IIc-46 IId-46 IIe-46 IIf-46

IIa-47 IIb-47 IIc-47 IId-47 IIe-47 IIf-47

IIa-48 IIb-48 IIc-48 IId-48 IIe-48 IIf-48

IIa-49 IIb-49 IIc-49 IId-49 IIe-49 IIf-49

IIa-50 IIb-50 IIc-50 IId-50 IIe-50 IIf-50  

TABLE 23

R¹ IIa IIb IIc IId IIe IIf

IIa-51 IIb-51 IIc-51 IId-51 IIe-51 IIf-51

IIa-52 IIb-52 IIc-52 IId-52 IIe-52 IIf-52

IIa-53 IIb-53 IIc-53 IId-53 IIe-53 IIf-53

IIa-54 IIb-54 IIc-54 IId-54 IIe-54 IIf-54

IIa-55 IIb-55 IIc-55 IId-55 IIe-55 IIf-55

IIa-56 IIb-56 IIc-56 IId-56 IIe-56 IIf-56

IIa-57 IIb-57 IIc-57 IId-57 IIe-57 IIf-57

IIa-58 IIb-58 IIc-58 IId-58 IIe-58 IIf-58

IIa-59 IIb-59 IIc-59 IId-59 IIe-59 IIf-59

IIa-60 IIb-60 IIc-60 IIe-60 IIe-60 IIf-60  

TABLE 24

R¹ IIa IIb IIc IId IIe IIf

IIa-61 IIb-61 IIc-61 IId-61 IIe-61 IIf-61

IIa-62 IIb-62 IIc-62 IId-62 IIe-62 IIf-62

IIa-63 IIb-63 IIc-63 IId-63 IIe-63 IIf-63

IIa-64 IIb-64 IIc-64 IId-64 IIe-64 IIf-64

IIa-65 IIb-65 IIc-65 IId-65 IIe-65 IIf-65

IIa-66 IIb-66 IIc-66 IId-66 IIe-66 IIf-66

IIa-67 IIb-67 IIc-67 IId-67 IIe-67 IIf-67

IIa-68 IIb-68 IIc-68 IId-68 IIe-68 IIf-68

IIa-69 IIb-69 IIc-69 IId-69 IIe-69 IIf-69

IIa-70 IIb-70 IIc-70 IId-70 IIe-70 IIf-70  

TABLE 25

R¹ IIa IIb IIc IId IIe IIf

IIa-71 IIb-71 IIc-71 IId-71 IIe-71 IIf-71

IIa-72 IIb-72 IIc-72 IId-72 IIe-72 IIf-72

IIa-73 IIb-73 IIc-73 IId-73 IIe-73 IIf-73

IIa-74 IIb-74 IIc-74 IId-74 IIe-74 IIf-74

IIa-75 IIb-75 IIc-75 IId-75 IIe-75 IIf-75

IIa-76 IIb-76 IIc-76 IId-76 IIe-76 IIf-76

IIa-77 IIb-77 IIc-77 IId-77 IIe-77 IIf-77

IIa-78 IIb-78 IIc-78 IId-78 IIe-78 IIf-78

IIa-79 IIb-79 IIc-79 IId-79 IIe-79 IIf-79

IIa-80 IIb-80 IIc-80 IId-80 IIe-80 IIf-80  

TABLE 26

R¹ IIa IIb IIc IId IIe IIf

IIa-81 IIb-81 IIc-81 IId-81 IIe-81 IIf-81

IIa-82 IIb-82 IIc-82 IId-82 IIe-82 IIf-82

IIa-83 IIb-83 IIc-83 IId-83 IIe-83 IIf-83

IIa-84 IIb-84 IIc-84 IId-84 IIe-84 IIf-84

IIa-85 IIb-85 IIc-85 IId-85 IIe-85 IIf-85

IIa-86 IIb-86 IIc-86 IId-86 IIe-86 IIf-86

IIa-87 IIb-87 IIc-87 IId-87 IIe-87 IIf-87

IIa-88 IIb-88 IIc-88 IId-88 IIe-88 IIf-88

IIa-89 IIb-89 IIc-89 IId-89 IIe-89 IIf-89

IIa-90 IIb-90 IIc-90 IId-90 IIe-90 IIf-90  

TABLE 27

R¹ IIa IIb IIc IId IIe IIf

IIa-91 IIb-91 IIc-91 IId-91 IIe-91 IIf-91

IIa-92 IIb-92 IIc-92 IId-92 IIe-92 IIf-92

IIa-93 IIb-93 IIc-93 IId-93 IIe-93 IIf-93

IIa-94 IIb-94 IIc-94 IId-94 IIe-94 IIf-94

IIa-95 IIb-95 IIc-95 IId-95 IIe-95 IIf-95

IIa-96 IIb-96 IIc-96 IId-96 IIe-96 IIf-96

IIa-97 IIb-97 IIc-97 IId-97 IIe-97 IIf-97

IIa-98 IIb-98 IIc-98 IId-98 IIe-98 IIf-98

IIa-99 IIb-99 IIc-99 IId-99 IIe-99 IIf-99

IIa-100 IIb-100 IIc-100 IId-100 IIe-100 IIf-100  

TABLE 28

R¹ IIa IIb IIc IId IIe IIf

IIa-101 IIb-101 IIc-101 IId-101 IIe-101 IIf-101

IIa-102 IIb-102 IIc-102 IId-102 IIe-102 IIf-102

IIa-103 IIb-103 IIc-103 IId-103 IIe-103 IIf-103

IIa-104 IIb-104 IIc-104 IId-104 IIe-104 IIf-104

IIa-105 IIb-105 IIc-105 IId-105 IIe-105 IIf-105

IIa-106 IIb-106 IIc-106 IId-106 IIe-106 IIf-106

IIa-107 IIb-107 IIc-107 IId-107 IIe-107 IIf-107

IIa-108 IIb-108 IIc-108 IId-108 IIe-108 IIf-108

IIa-109 IIb-109 IIc-109 IId-109 IIe-109 IIf-109

IIa-110 IIb-110 IIc-110 IId-110 IIe-110 IIf-110  

TABLE 29

R¹ IIa IIb IIc IId IIe IIf

IIa-111 IIb-111 IIc-111 IId-111 IIe-111 IIf-111

IIa-112 IIb-112 IIc-112 IId-112 IIe-112 IIf-112

IIa-113 IIb-113 IIc-113 IId-113 IIe-113 IIf-113

IIa-114 IIb-114 IIc-114 IId-114 IIe-114 IIf-114

IIa-115 IIb-115 IIc-115 IId-115 IIe-115 IIf-115

IIa-116 IIb-116 IIc-116 IId-116 IIe-116 IIf-116

IIa-117 IIb-117 IIc-117 IId-117 IIe-117 IIf-117

IIa-118 IIb-118 IIc-118 IId-118 IIe-118 IIf-118

IIa-119 IIb-119 IIc-119 IId-119 IIe-119 IIf-119

IIa-120 IIb-120 IIc-120 IId-120 IIe-120 IIf-120  

TABLE 30

R¹ IIa IIb IIc IId IIe IIf

IIa-121 IIb-121 IIc-121 IId-121 IIe-121 IIf-121

IIa-122 IIb-122 IIc-122 IId-122 IIe-122 IIf-122

IIa-123 IIb-123 IIc-123 IId-123 IIe-123 IIf-123

IIa-124 IIb-124 IIc-124 IId-124 IIe-124 IIf-124

IIa-125 IIb-125 IIc-125 IId-125 IIe-125 IIf-125

IIa-126 IIb-126 IIc-126 IId-126 IIe-126 IIf-126

IIa-127 IIb-127 IIc-127 IId-127 IIe-127 IIf-127

IIa-128 IIb-128 IIc-128 IId-128 IIe-128 IIf-128

IIa-129 IIb-129 IIc-129 IId-129 IIe-129 IIf-129

IIa-130 IIb-130 IIc-130 IId-130 IIe-130 IIf-130  

TABLE 31

R¹ IIa IIb IIc IId IIe IIf

IIa-131 IIb-131 IIc-131 IId-131 IIe-131 IIf-131

IIa-132 IIb-132 IIc-132 IId-132 IIe-132 IIf-132

IIa-133 IIb-133 IIc-133 IId-133 IIe-133 IIf-133

IIa-134 IIb-134 IIc-134 IId-134 IIe-134 IIf-134

IIa-135 IIb-135 IIc-135 IId-135 IIe-135 IIf-135

IIa-136 IIb-136 IIc-136 IId-136 IIe-136 IIf-136

IIa-137 IIb-137 IIc-137 IId-137 IIe-137 IIf-137

IIa-138 IIb-138 IIc-138 IId-138 IIe-138 IIf-138

IIa-139 IIb-139 IIc-139 IId-139 IIe-139 IIf-139

IIa-140 IIb-140 IIc-140 IId-140 IIe-140 IIf-140  

TABLE 32

R¹ IIa IIb IIc IId IIe IIf

IIa-141 IIb-141 IIc-141 IId-141 IIe-141 IIf-141

IIa-142 IIb-142 IIc-142 IId-142 IIe-142 IIf-142

IIa-143 IIb-143 IIc-143 IId-143 IIe-143 IIf-143

IIa-144 IIb-144 IIc-144 IId-144 IIe-144 IIf-144

IIa-145 IIb-145 IIc-145 IId-145 IIe-145 IIf-145

IIa-146 IIb-146 IIc-146 IId-146 IIe-146 IIf-146

IIa-147 IIb-147 IIc-147 IId-147 IIe-147 IIf-147

IIa-148 IIb-148 IIc-148 IId-148 IIe-148 IIf-148

IIa-149 IIb-149 IIc-149 IId-149 IIe-149 IIf-149

IIa-150 IIb-150 IIc-150 IId-150 IIe-150 IIf-150  

TABLE 33

R¹ IIa IIb IIc IId IIe IIf

IIa-151 IIb-151 IIc-151 IId-151 IIe-151 IIf-151

IIa-152 IIb-152 IIc-152 IId-152 IIe-152 IIf-152

IIa-153 IIb-153 IIc-153 IId-153 IIe-153 IIf-153

IIa-154 IIb-154 IIc-154 IId-154 IIe-154 IIf-154

IIa-155 IIb-155 IIc-155 IId-155 IIe-155 IIf-155

IIa-156 IIb-156 IIc-156 IId-156 IIe-156 IIf-156

IIa-157 IIb-157 IIc-157 IId-157 IIe-157 IIf-157

IIa-158 IIb-158 IIc-158 IId-158 IIe-158 IIf-158

IIa-159 IIb-159 IIc-159 IId-159 IIe-159 IIf-159

IIa-160 IIb-160 IIc-160 IId-160 IIe-160 IIf-160  

TABLE 34

R¹ IIa IIb IIc IId IIe IIf

IIa-161 IIb-161 IIc-161 IId-161 IIe-161 IIf-161

IIa-162 IIb-162 IIc-162 IId-162 IIe-162 IIf-162

IIa-163 IIb-163 IIc-163 IId-163 IIe-163 IIf-163

IIa-164 IIb-164 IIc-164 IId-164 IIe-164 IIf-164

IIa-165 IIb-165 IIc-165 IId-165 IIe-165 IIf-165

IIa-166 IIb-166 IIc-166 IId-166 IIe-166 IIf-166  

TABLE 35 Compound No. Physical property Ia-04 mp 175-178° C.; ¹H-NMR (CDCl₃—CD₃OD) δ 1.04 (1H, m), 1.25-1.49 (10H, m), 1.57-1.66 (2H, m), 2.00 (1H, m), 2.15-2.22 (2H, m), 2.51 (1H, m), 3.82 (1H, m), 5.77 (1H, dt, J = 15.9, 1.5 Hz), 6.41 (1H, d, J = 7.8 Hz), 6.95 (1H, dt, J = 15.9, 7.1 Hz), 7.34 (1H, dd, J = 3.0, 4.8 Hz), 7.41 (1H, dd, J = 1.5, 4.8 Hz), 7.90 (1H, dd, J = 1.5, 3.0 Hz); IR (Nujol) 3363, 3105, 2627, 1697, 1618, 1554, 1248 cm⁻¹; [α]_(D) ²⁵ + 44.3 ± 0.8° (c = 1.011, MeOH); Anal. (C₁₉H₂₅NO₃S) Calcd. (%): C, 65.68; H, 7.25; N, 4.03; S, 9.23 Found (%): C, 65.58; H, 7.18; N, 4.03; S, 9.18 Ia-17 mp 155-157° C.; ¹H-NMR (CDCl₃—CD₃OD) δ 1.04 (1H, m), 1.22-1.53 (10H, m), 1.60-1.71 (2H, m), 2.02 (1H, m), 2.17-2.23 (2H, m), 2.58 (1H, m), 3.92 (1H, m), 5.78 (1H, dt, J = 15.6, 1.5 Hz), 6.33 (1H, d, J = 7.5 Hz), 6.97 (1H, dt, J = 15.6, 6.9 Hz), 7.38-7.49 (2H, m), 7.86-7.89 (3H, m), 8.30 (1H, dd, J = 0.9, 6.9 Hz); IR (Nujol) 3276, 2671, 1693, 1622, 1529, 1421, 1377, 1298, 1277, 1254 cm⁻¹; [α]_(D) ²⁵ + 38.5 ± 0.8° (c = 1.018, MeOH); Anal. (C₂₃H₂₇NO₃S.0.2H₂O) Calcd. (%): C, 68.87; H, 6.88; N, 3.49; S, 7.99 Found (%): C, 68.93; H, 7.01; N, 3.55; S, 7.87 Ia-20 mp 129-131° C.; ¹H-NMR (CDCl₃) δ 1.01 (1H, m), 1.26-1.52 (10H, m), 1.60-1.66 (2H, m), 2.02 (1H, m), 2.18-2.25 (2H, m), 2.49 (3H, s), 2.58 (1H, m), 3.95 (1H, m), 5.80 (1H, d, J = 15.6 Hz), 6.06 (1H, d, J = 7.8 Hz), 7.04 (1H, dt, J = 15.6, 7.1 Hz), 7.23 (1H, dd, J = 1.2, 8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.80 (1H, s), 8.14 (1H, s); IR (Nujol) 3269, 3078, 2677, 1697, 1649, 1624, 1539, 1437, 1377, 1298, 1281 cm⁻¹; [α]_(D) ²⁵ + 32.0 ± 0.7° (c = 1.005, MeOH); Anal. (C₂₄H₂₉NO₃S) Calcd. (%): C, 70.04; H, 7.10; N, 3.40; S, 7.79 Found (%): C, 69.83; H, 7.10; N, 3.43; S, 7.64 Ia-28 mp 138-140° C.; ¹H-NMR (CDCl₃) δ 1.02 (1H, m), 1.21-1.52 (10H, m), 1.59-1.70 (2H, m), 2.01 (1H, m), 2.17-2.24 (2H, m), 2.56 (1H, m), 3.92 (1H, m), 5.79 (1H, dt, J = 15.6, 1.5 Hz), 6.14 (1H, d, J = 8.1 Hz), 7.03 (1H, dt, J = 15.6, 7.1 Hz), 7.16 (1H, td, J = 8.6, 2.7 Hz), 7.77 (1H, dd, J = 4.8, 8.6 Hz), 7.91 (1H, s), 8.07 (1H, dd, J = 2.7, 10.2 Hz); IR (Nujol) 3276, 2671, 1695, 1624, 1533, 1442, 1433, 1296, 1277, 1246, 1200 cm⁻¹; [α]_(D) ²⁵ + 35.6 ± 0.8° (c = 1.014, MeOH); Anal. (C₂₃H₂₆FNO₃S.0.2H₂O) Calcd. (%): C, 65.91; H, 6.35; F, 4.53; N, 3.34; S, 7.65 Found (%): C, 65.99; H, 6.38; F, 4.42; N, 3.39; S, 7.57 Ia-34 mp 172-173° C.; ¹H-NMR (CDCl₃—CD₃OD) δ 1.08 (1H, m), 1.29-1.55 (10H, m), 1.60-1.69 (2H, m), 2.03 (1H, m), 2.14-2.21 (2H, m), 2.60 (1H, m), 3.96 (1H, m), 5.76 (1H, dt, J = 15.6, 1.5 Hz), 6.57 (1H, d, J = 7.5 Hz), 6.97 (1H, dt, J = 15.6, 7.1 Hz), 7.38 (1H, d, J = 5.7 Hz), 7.42 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 5.7 Hz), 7.65 (1H, d, J = 6.9 Hz), 7.95 (1H, d, J = 7.8 Hz); IR (Nujol) 3302, 2698, 1739, 1693, 1657, 1622, 1581, 1568, 1547, 1205 cm⁻¹; [α]_(D) ²⁵ + 35.0 ± 0.7° (c = 1.013, MeOH); Anal. (C₂₃H₂₇NO₃S.0.2H₂O) Calcd. (%): C, 68.87; H, 6.88; N, 3.49; S, 7.99 Found (%): C, 68.92; H, 7.05; N, 3.44; S, 7.67  

TABLE 36 Compound No. Physical property Ia-49 ¹H-NMR (CDCl₃) δ 1.02 (1H, m), 1.29-1.74 (12H, m), 2.02 (1H, m), 2.17-2.24 (2H, m), 2.56 (1H, m), 3.44 (3H, s), 3.96 (1H, m), 4.79 (2H, s), 5.79 (1H, dt, J = 15.6, 1.2 Hz), 5.98 (1H, d, J = 7.8 Hz), 7.01 (1H, dt, J = 15.6, 7.2 Hz), 7.33-7.40 (2H, m), 7.77 (1H, dd, J = 7.2, 2.4 Hz), 8.14 (1H, s); IR (CHCl₃) 3442, 2682, 1695, 1652, 1573, 1508, 1425, 1284, 1205, 1120 cm⁻¹; [α]_(D) ^(25.0) + 31.0 ± 0.7° (c = 1.009, MeOH); Anal. (C₂₅H₃₁NO₅.0.5H₂O) Calcd. (%): C, 69.10; H, 7.42; N, 3.22 Found (%): C, 68.83; H, 7.48; N, 3.30 Ia-51 ¹H-NMR (CDCl₃—CD₃OD) δ 1.03 (1H, m), 1.20-1.51 (9H, m), 1.59- 1.71 (3H, m), 2.01 (1H, d, J = 3.6 Hz), 2.15-2.22 (2H, m), 2.56 (1H, s), 3.90 (1H, m), 5.77 (1H, d, J = 15.6 Hz), 6.90 (1H, dd, J = 2.1, 8.4 Hz), 6.96 (1H, dt, J = 15.6, 6.9 Hz), 6.99 (1H, d, J = 2.1 Hz), 7.58 (1H, d, J = 8.4 Hz), 8.01 (1H, s); IR (KBr) 3350, 3141, 1695, 1628, 1560, 1523, 1493, 1441, 1367, 1279, 1225, 1136, 1124 cm⁻¹; [α]_(D) ²⁷ + 26.6 ± 0.7° (c = 1.008, MeOH); Anal. (C₂₃H₂₇NO₅.0.3H₂O) Calcd. (%): C, 68.57; H, 6.91; N, 3.48 Found (%): C, 68.47; H, 6.91; N, 3.66 Ia-52 ¹H-NMR (CDCl₃—CD₃OD) δ 1.02 (1H, m), 1.22-1.48 (9H, m), 1.57- 1.60 (3H, m), 1.98 (1H, d, J = 3.3 Hz), 2.11-2.18 (2H, m), 2.53 (1H, s), 3.89 (1H, m), 5.75 (1H, dd, J = 1.5, 15.3 Hz), 6.31 (1H, d, J = 7.8 Hz), 6.90 (1H, dd, J = 2.4, 8.7 Hz), 6.96 (1H, dt, J = 15.3, 6.9 Hz), 7.33 (1H, d, J = 8.7 Hz), 7.43 (1H, d, J = 2.4 Hz), 8.07 (1H, s); IR (KBr) 3347, 1695, 1635, 1558, 1524, 1462, 1309, 1271, 1192, 1173, 1134 cm⁻¹; [α]_(D) ²⁵ + 20.1 ± 0.6° (c = 1.013, MeOH); Anal. (C₂₃H₂₇NO₅.0.4H₂O) Calcd. (%): C, 68.27; H, 6.92; N, 3.46 Found (%): C, 68.12; H, 7.00; N, 3.59 Ia-54 ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.23-1.72 (10H, m), 2.02 (1H, m), 2.18-2.25 (2H, m), 2.55 (1H, m), 3.94 (1H, m), 5.79 (1H, dt, J = 15.6, 1.5 Hz), 5.91 (1H, d, J = 8.1 Hz), 7.03 (1H, dt, J = 15.6, 6.9 Hz), 7.09-7.16 (1H, m), 7.25 (1H, dd, J = 9.0, 1.8 Hz), 7.84 (1H, dd, J = 9.0, 5.4 Hz), 8.06 (1H, s); IR (CHCl₃) 3442, 2680, 1695, 1652, 1563, 1506, 1257, 1224, 1218, 1133, cm⁻¹; [α]_(D) ^(25.0) + 25.4 ± 0.7° (c = 1.005, MeOH); Anal. (C₂₃H₂₈FNO₄.0.1H₂O) Calcd. (%): C, 68.85; H, 6.58; F, 4.73; N, 3.49 Found (%): C, 68.65; H, 6.43; F, 4.59; N, 3.60 Ia-56 ¹H-NMR (CDCl₃) δ 1.12 (1H, m), 1.29-1.53 (9H, m), 1.60-1.74 (3H, m), 2.04 (1H, d, J = 3.6 Hz), 2.16-2.22 (2H, m), 2.57 (1H, s), 4.03 (1H, m), 5.77 (1H, d, J = 15.6 Hz), 6.89 (1H, d, J = 2.1 Hz), 7.02 (1H, dt, J = 15.3, 7.2 Hz), 7.36 (1H, t, J = 7.5 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.74 (1H, dd, J = 1.2, 7.5 Hz), 7.74 (1H, d, J = 2.1 Hz), 8.11 (1H, dd, J = 1.2, 7.5 Hz); IR (CHCl₃) 3435, 2679, 1695, 1653, 1595, 1547, 1533, 1475, 1458, 1421, 1306, 1286, 1167, 1120 cm⁻¹; [α]_(D) ^(25.5) + 47.7 ± 0.9° (c = 1.003, MeOH); Anal. (C₂₃H₂₇NO₄0.1H₂O) Calcd. (%): C, 72.08; H, 7.15; N, 3.65 Found (%): C, 72.01; H, 7.11; N, 3.72  

TABLE 37 Compound No. Physical property Ia-65 ¹H-NMR (CDCl₃) δ 1.02 (1H, m), 1.27-1.71 (12H, m), 2.01 (1H, d, J = 3.9 Hz), 2.16-2.23 (2H, m), 2.48 (1H, br s), 3.92 (1H, m), 5.81 (1H, d, J = 15.6 Hz), 6.08 (1H, d, J = 8.4 Hz), 6.80 (1H, d, J = 1.5 Hz), 6.98 (1H, dt, J = 5.4 and 0.6 Hz), 7.03 (1H, dt, J = 15.6 and 6.9 Hz), 10.49 (1H, s); IR (CHCl₃) 3446, 3215, 1726, 1693, 1643, 1541, 1504, 1477, 1462, 1402, 1373, 1303, 1248 cm⁻¹; [α]_(D) ²⁶ + 67.8 ± 1.1° (c = 1.002, MeOH) Anal. (C₂₁H₂₆N₂O₃S.0.25CH₃COOEt) Calcd. (%): C, 63.43; H, 6.77; N, 6.72; S, 7.69 Found (%): C, 63.66; H, 6.60; N, 6.93; S, 7.60 Ia-66 ¹H-NMR (CDCl₃) δ 1.02 (1H, m), 1.27-1.70 (12H, m), 2.01 (1H, d, J = 3.6 Hz), 2.15-2.22 (2H, m), 2.51 (1H, br s), 3.92 (1H, m), 5.80 (1H, d, J = 15.6 Hz), 6.08 (1H, d, J = 7.8 Hz), 6.77 (1H, d, J = 2.1 Hz), 6.88 (1H, d, J = 5.4 Hz), 6.95 (1H, d, J = 5.4 Hz), 7.03 (1H, dt, J = 15.6 and 6.9 Hz), 11.07 (1H, s); IR (CHCl₃) 3444, 3191, 2677, 1693, 1639, 1543, 1518, 1475, 1458, 1421, 1396, 1378, 1296, 1279, 1255 cm⁻¹; [α]_(D) ²⁶ + 55.3 ± 1.0° (c = 1.001, MeOH) Anal. (C₂₁H₂₆N₂O₃S.0.3H₂O) Calcd. (%): C, 64.36; H, 6.84; N, 7.15; S, 8.18 Found (%): C, 64.22; H, 6.48; N, 7.13; S, 8.22 Ia-95 mp 113-114° C.; ¹H-NMR (CDCl₃—DMSO—d₆) δ 1.12 (1H, m), 1.26 (3H, t, J = 6.9 Hz), 1.27-1.64 (12H, m), 2.01 (1H, m), 2.15-2.22 (2H, m), 2.57 (1H, br s), 3.90 (1H, m), 4.14 (2H, q, J = 6.9 Hz), 4.48 (2H, br s), 5.57 (1H, br s), 5.77 (1H, d, J = 15.6 Hz), 6.68 (1H, br s), 6.92 (1H, dd, J = 15.6, 7.2 Hz), 7.38 (1H, br d, J = 8.1 Hz), 7.81 (1H, d, J = 8.1 Hz), 7.95 (1H, s), 8.33 (1H, br s); IR (CHCl₃) 3446, 1703, 1653, 1514, 1435, 1300, 1223, 1134 cm⁻¹; [α]_(D) ²³ + 5.5 ± 0.5° (c = 1.008, MeOH) Anal. (C₂₇H₃₄N₂O₅S.0.3H₂O) Calcd. (%): C, 64.34; H, 6.92; N, 5.56; S, 6.36 Found (%): C, 64.27; H, 6.69; N, 5.54; S, 6.37 Ic-04 mp 105-107° C.; ¹H-NMR (CDCl₃) δ 1.02 (1H, m), 1.20-1.70 (12H, m), 2.00 (1H, m), 2.49 (1H, br s), 3.47-3.58 (2H, m), 3.91 (1H, m), 4.04 (2H, s), 6.07 (1H, d, J = 7.2 Hz), 7.34 (1H, dd, J = 3.0, 5.1 Hz), 7.37 (1H, dd, J = 1.5, 5.1 Hz), 7.88 (1H, dd, J = 1.5, 3.0 Hz); IR (Nujol) 3354, 3093, 2553, 1730, 1612, 1556, 1240, 1138 cm⁻¹; [α]_(D) ²⁵ + 46.6 ± 0.9° (c = 1.009, MeOH); Anal. (C₁₈H₂₅NO₄S) Calcd. (%): C, 61.51; H, 7.17; N, 3.99; S, 9.12 Found (%): C, 61.45; H, 7.32; N, 4.06; S, 9.10 Ic-17 mp 149-151° C.; ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.21-1.72 (12H, m), 2.02 (1H, m), 2.57 (1H, br s), 3.47-3.58 (2H, m), 3.98 (1H, m), 4.03 (2H, s), 6.14 (1H, d, J = 7.8 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.44 (1H, dt, J = 1.2, 7.5 Hz), 7.46 (1H, dt, J = 1.2, 7.5 Hz), 7.87 (1H, dd, J = 1.2, 7.5 Hz), 7.88 (1H, s), 8.29 (1H, dd, J = 1.2, 7.5 Hz); IR (Nujol) 3296, 2528, 1726, 1604, 1558, 1240, 1228, 1140 cm⁻¹; [α]_(D) ²⁵ + 38.1 ± 0.8° (c = 1.013, MeOH); Anal. (C₂₂H₂₇NO₄S) Calcd. (%): C, 65.18; H, 6.78; N, 3.49; S, 7.99 Found (%): C, 65.62; H, 7.06; N, 3.51; S, 7.78  

TABLE 38 Compound No. Physical property Ic-19 mp 145-147° C.; ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.21-1.33 (2H, m), 1.40-1.71 (10H, m), 2.01 (1H, m), 2.48 (3H, s), 2.6 (1H, br s), 3.47-3.58 (2H, m), 3.97 (1H, m), 4.03 (2H, s), 6.12 (1H, d, J = 7.8 Hz), 7.28 (1H, m), 7.65 (1H, m), 7.78 (1H, s), 8.15 (1H, d, J = 8.4 Hz); IR (Nujol) 3288, 2521, 1724, 1601, 1560, 1225, 1138 cm⁻¹; [α]_(D) ²⁵ + 36.8 ± 0.8° (c = 1.008, MeOH) Anal. (C₂₃H₂₉NO₄S) Calcd. (%): C, 66.48; H, 7.03; N, 3.37; S, 7.72 Found (%): C, 66.33; H, 7.03; N, 3.30; S, 7.43 Ic-20 mp 135-136° C.; ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.21-1.72 (12H, m), 2.02 (1H, m), 2.49 (3H, s), 2.57 (1H, br s), 3.48-3.59 (2H, m), 3.97 (1H, m), 4.03 (2H, s), 6.12 (1H, d, J = 7.5 Hz), 7.23 (1H, dd, J = 1.5, 8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.83 (1H, s), 8.12 (1H, d, J = 1.5 Hz); IR (Nujol) 3384, 3361, 2546, 1736, 1718, 1616, 1533, 1225, 1140 cm⁻¹; [α]_(D) ²⁵ + 32.4 ± 0.7° (c = 1.003, MeOH); Anal. (C₂₃H₂₉NO₄S) Calcd. (%): C, 66.48; H, 7.03; N, 3.37; S, 7.72 Found (%): C, 66.31; H, 7.32; N, 3.34; S, 7.60 Ic-22 mp 76-79° C.; ¹H-NMR (CDCl₃—CD₃OD) δ 1.07 (1H, m), 1.20-1.32 (2H, m), 1.34-1.70 (10H, m), 2.00 (1H, m), 2.57 (1H, br s), 3.44- 3.55 (2H, m), 3.88 (1H, m), 4.00 (2H, s), 6.43 (1H, d, J = 7.8 Hz), 6.97 (1H, dd, J = 2.4 and 8.7 Hz), 7.25 (1H, d, J = 2.4 Hz), 7.65 (1H, s), 8.06 (1H, d, J = 8.7 Hz); IR (CHCl₃) 3599, 3437, 1780, 1649, 1603, 1516, 1124 cm⁻¹; [α]_(D) ²⁵ + 36.4 ± 0.8° (c = 1.013, MeOH) Anal. (C₂₂H₂₇NO₅S.0.6H₂O) Calcd. (%): C, 61.69; H, 6.64; N, 3.27; S, 7.49 Found (%): C, 61.58; H, 6.37; N, 3.54; S, 7.48 Ic-23 mp 149-151° C.; ¹H-NMR (CDCl₃) δ 1.08 (1H, m), 1.21-1.86 (12H, m), 1.99 (1H, m), 2.22 (2H, br s), 2.56 (1H, m), 3.53 (2H, t, J = 6.0 Hz), 3.92 (1H, m), 4.03 (2H, s), 6.31 (1H, d, J = 7.2 Hz), 7.00 (1H, dd, J = 2.1, 8.7 Hz), 7.67 (1H, d, J = 8.7 Hz), 7.72 (1H, d, J = 2.4 Hz), 7.83 (1H, s); IR (Nujol) 3313, 3104, 2636, 1743, 1626, 1599, 1552, 1439, 1248, 1190, 1153, 1124 cm⁻¹; [α]_(D) ²⁶ + 33.6 ± 0.7° (c = 1.002%, MeOH); Anal. (C₂₂H₂₇NO₅S) Calcd. (%): C, 63.29; H, 6.52; N, 3.35; S, 7.68 Found (%): C, 62.99; H, 6.66; N, 3.39; S, 7.57 Ic-28 mp 149-151° C.; ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.21-1.72 (12H, m), 2.03 (1H, m), 2.56 (1H, br s), 3.48-3.60 (2H, m), 3.95 (1H, m), 4.04 (2H, s), 6.11 (1H, d, J = 8.1 Hz), 7.16 (1H, dt, J = 2.4, 8.7 Hz), 7.78 (1H, dd, J = 4.8, 8.7 Hz), 7.92 (1H, s), 8.05 (1H, dd, J = 2.4, 9.9 Hz); IR (Nujol) 3384, 3361, 2546, 1736, 1718, 1616, 1533, 1225, 1140 cm⁻¹; [α]_(D) ²⁵ + 35.6 ± 0.8° (c = 1.014, MeOH); Anal. (C₂₂H₂₆FNO₄S) Calcd. (%): C, 62.99; H, 6.25; F, 4.53; N, 3.34; S, 7.64 Found (%): C, 62.84; H, 6.51; F, 4.44; N, 3.41; S, 7.40 Ic-34 mp 154-157° C.; ¹H-NMR (CDCl₃) δ 1.09 (1H, m), 1.24-1.72 (12H, m), 2.04 (1H, m), 2.59 (1H, br s), 3.47-3.58 (2H, m), 4.02 (1H, m), 4.02 (2H, s), 6.42 (1H, d, J = 7.5 Hz), 7.38 (1H, d, J = 5.4 Hz), 7.43 (1H, d, J = 7.5 Hz), 7.59 (1H, d, J = 5.4 Hz), 7.61 (1H, d, J = 7.5 Hz), 7.96 (1H, dd, J = 0.9, 7.5 Hz); IR (Nujol) 3288, 2540, 1726, 1614, 1577, 1554, 1319, 1244, 1225, 1138 cm⁻¹; [α]_(D) ²⁵ + 39.8 ± 0.8° (c = 1.017, MeOH); Anal. (C₂₂H₂₇NO₄S) Calcd. (%): C, 65.81; H, 6.78; N, 3.49; S, 7.99 Found % C, 65.53; H, 6.94; N, 3.52; S, 7.76  

TABLE 39 Compound No. Physical property Ic-39 ¹H-NMR (CDCl₃) δ 1.10 (1H, m), 1.25-1.71 (12H, m), 2.03 (1H, m), 2.58 (1H, br s), 3.49-3.56 (2H, m), 3.98 (3H, s), 4.02 (2H, s), 4.03 (1H, m), 6.40 (1H, d, J = 8.4 Hz), 6.42 (2H, s), 7.42 (1H, t, J = 7.5 Hz), 7.66 (1H, d, J = 7.5 Hz), 7.93 (1H, d, J = 7.5 Hz); IR (CHCl₃) 3451, 1780, 1732, 1649, 1508, 1373, 1220, 1151 cm⁻¹; [α]_(D) ²⁴ + 37.0 ± 0.8° (c = 1.008, MeOH); Anal. (C₂₃H₂₉NO₅S.0.3H₂O) Calcd. (%): C, 63.22; H, 6.83; N, 3.21; S, 7.34 Found (%): C, 63.26; H, 6.78; N, 3.23; S, 7.17 Ic-49 ¹H-NMR (CDCl₃) δ 1.06 (1H, m), 1.29-1.36 (2H, m), 1.36-1.74 (10H, m), 2.03 (1H, m), 2.53 (1H, m), 3.45 (3H, s), 3.52 (2H, dt, J = 6.3, 1.5 Hz), 4.00 (1H, m), 4.02 (2H, s), 4.79 (2H, s), 6.07 (1H, d, J = 7.8 Hz), 7.33-7.40 (2H, m), 7.77 (1H, dd, J = 6.9, 2.1 Hz), 8.16 (1H, s); IR (CHCl₃) 3440, 2829, 1652, 1573, 1509, 1226, 1205, 1124 cm⁻¹; [α]_(D) ^(25.0) + 33.3 ± 0.7° (c = 1.016, MeOH); Anal. (C₂₄H₃₁NO₆) Calcd. (%): C, 67.11; H, 7.27; N, 3.26 Found (%): C, 66.82; H, 7.39; N, 3.32 Ic-51 ¹H-NMR (CDCl₃—CD₃OD) δ 1.08 (1H, m), 1.25-1.28 (2H, m), 1.37- 1.62 (10H, m), 1.99 (1H, d, J = 3.3 Hz), 2.54 (1H, s), 3.45-3.49 (2H, m), 3.87 (1H, m), 4.00 (2H, s), 6.44 (1H, d, J = 7.8 Hz), 6.88 (1H, dd, J = 2.1, 8.7 Hz), 6.97 (1H, d, J = 2.1 Hz), 7.60 (1H, d, J = 8.7 Hz), 8.02 (1H, s); IR (KBr) 3365, 3140, 1734, 1628, 1560, 1527, 1493, 1440, 1363, 1279, 1220, 1136, 1124 cm⁻¹; [α]_(D) ²⁷ + 29.1 ± 0.7° (c = 1.016, MeOH); Anal. (C₂₂H₂₇NO₆.0.5H₂O) Calcd. (%): C, 64.38; H, 6.88; N, 3.41 Found (%): C, 64.39; H, 6.95; N, 3.66 Ic-52 ¹H-NMR (CDCl₃—CD₃OD) δ 1.07 (1H, m), 1.24-1.30 (3H, m), 1.45- 1.49 (5H, m), 1.59-1.65 (4H, m), 2.00 (1H, d, J = 3.3 Hz), 2.59 (1H, s), 3.52 (2H, t, J = 6.0 Hz), 3.89 (1H, m), 4.00 (1H, d, J = 16.5 Hz), 4.06 (1H, d, J = 16.5 Hz), 6.14 (1H, d, J = 8.1 Hz), 6.90 (1H, dd, J = 2.1, 9.0 Hz), 7.34 (1H, d, J = 2.1 Hz), 7.36 (1H, d, J = 9.0 Hz), 8.06 (1H, s); IR (CHCl₃) 3438, 3267, 1730, 1647, 1620, 1558, 1514, 1468, 1169, 1134 cm⁻¹; [α]_(D) ²⁷ + 25.0 ± 0.7° (c = 1.003, MeOH); Anal. (C₂₂H₂₇NO₆.0.3H₂O) Calcd. (%): C, 64.95; H, 6.84; N, 3.44 Found (%): C, 64.84; H, 6.96; N, 3.62 Ic-54 ¹H-NMR (CDCl₃) δ 1.04 (1H, m), 1.25-1.32 (2H, m), 1.43-1.68 (10H, m), 2.03 (1H, m), 2.53 (1H, m), 3.53 (2H, t, J = 6.6 Hz), 3.96 (1H, m), 4.04 (2H, s), 6.04 (1H, d, J = 8.1 Hz), 7.09-7.16 (1H, m), 7.25 (1H, dd, J = 8.4, 2.4 Hz), 7.84 (1H, dd, J = 8.4, 5.7 Hz), 8.10 (1H, s); IR (CHCl₃) 3440, 2875, 1656, 1563, 1506, 1224, 1216, 1205 cm⁻¹; [α]_(D) ^(26.0) + 27.6 ± 0.7° (c = 1.018, MeOH); Anal. (C₂₂H₂₆FNO₅.0.6H₂O) Calcd. (%): C, 63.79; H, 6.62; F, 4.59; N, 3.38 Found (%): C, 63.48; H, 6.49; F, 4.47; N, 3.59 Ic-65 mp 148-149° C.; ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.27-1.30 (2H, m), 1.41-1.52 (6H, m), 1.59-1.71 (4H, m), 2.01 (1H, d, J = 3.3 Hz), 2.45 (1H, s), 3.53 (2H, dt, J = 1.5, 6.3 Hz), 3.94 (1H, m), 4.07 (2H, s), 6.13 (1H, d, J = 8.1 Hz), 6.78 (1H, d, J = 1.5 Hz), 6.98 (1H, d, J = 5.1 Hz), 7.23 (1H, d, J = 8.1 Hz), 10.27 (1H, s); IR (KBr) 3367, 3292, 3111, 2758, 2636, 2544, 1712, 1601, 1574, 1510, 1458, 1325, 1250, 1225, 1138 cm⁻¹; [α]_(D) ²⁵ + 66.6 ± 1.1° (c = 1.008, MeOH); Anal. (C₂₀H₂₆N₂O₄S.0.1H₂O) Calcd. (%): C, 61.23; H, 6.68; N, 7.14; S, 8.17 Found (%): C, 61.20; H, 6.79; N, 7.25; S, 8.25  

TABLE 40 Compound No. Physical property Ic-66 mp 143-144° C.; ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.24-1.30 (2H, m), 1.38-1.52 (6H, m), 1.59-1.67 (4H, m), 2.01 (1H, d, J = 3.0 Hz), 2.48 (1H, s), 3.52 (2H, t, J = 6.3 Hz), 3.94 (1H, m), 4.07 (2H, s), 6.12 (1H, d, J = 8.4 Hz), 6.73 (1H, d, J = 1.8 Hz), 6.88 (1H, d, J = 5.4 Hz), 6.93 (1H, d, J = 5.4 Hz), 10.80 (1H, s); IR (KBr) 3348, 3105, 2754, 2648, 2551, 1738, 1587, 1556, 1520, 1437, 1425, 1223, 1146 cm⁻¹; [α]_(D) ²⁵ + 50.5 ± 0.9° (c = 1.014, MeOH); Anal. (C₂₀H₂₆N₂O₄S.0.1H₂O) Calcd. (%): C, 61.23; H, 6.68; N, 7.14; S, 8.17 Found (%): C, 61.13; H, 6.79; N, 7.17; S, 8.07 Ic-81 ¹H-NMR (CDCl₃—CD₃OD) δ 1.06 (1H, m), 1.20-1.28 (2H, m), 1.34- 1.49 (6H, m), 1.55-1.63 (4H, m), 1.95 (1H, d, J = 3.6 Hz), 2.42 (3H, s), 2.56 (1H, brs), 3.48 (2H, t, J = 6.5 Hz), 3.84 (1H, br s), 4.01 (2H, s), 6.37 (1H, d, J = 7.5 Hz), 6.71 (1H, d, J = 2.1 Hz), 7.16 (1H, d, J = 2.1 Hz), 8.10 (1H, s); IR (KBr) 3361, 3134, 1734, 1635, 1560, 1529, 1458, 1415, 1362, 1288, 1198, 1165, 1136 cm⁻¹; [α]_(D) ²⁴ + 28.1 ± 0.7° (c = 1.012, MeOH) Anal. (C₂₃H₂₉NO₆.0.5H₂O) Calcd. (%): C, 65.08; H, 7.12; N, 3.30 Found (%): C, 65.14; H, 7.06; N, 3.43 Ic-84 mp 133-135° C.; ¹H-NMR (CDCl₃) δ 1.09 (1H, m), 1.22-1.70 (12H, m), 2.01 (1H, d, J = 3.3 Hz), 2.55 (1H, br s), 3.50-3.68 (2H, m), 3.96-4.09 (3H, m), 4.21-4.35 (2H, m), 6.11 (1H, m), 7.64 (1H, dd, J = 1.8, 8.7 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.85 (1H, br s), 8.18 (1H, br s); IR (Nujol) 3323, 2924, 1736, 1599, 1562, 1514, 1448, 1281, 1217, 1142 cm⁻¹; [α]_(D) ²⁴ + 21.7 ± 0.6° (c = 1.017%, MeOH); Anal. (C₂₅H₃₂N₂O₆S) Calcd. (%): C, 61.45; H, 6.60; N, 5.73; S, 6.56 Found (%): C, 61.26; H, 6.41; N, 5.70; S, 6.48 Ic-86 ¹H-NMR (CDCl₃) δ 1.16-1.69 (13H, m), 1.92 (1H, br s), 2.39 (1H, br s), 3.41 (2H, t, J = 5.4 Hz), 3.68 (1H, m), 3.92 (2H, s), 5.83 (2H, s), 7.65 (1H, dd, J = 2.1, 8.7 Hz), 7.83 (1H, d, J = 8.7 Hz), 8.23 (1H, d, J = 8.4 Hz), 8.25 (1H, s), 8.27 (1H, d, J = 2.1 Hz), 8.77 (1H, s), 12.53 (1H, br s); IR (Nujol) 3332, 2924, 1724, 1680, 1631, 1572, 1529, 1444, 1375, 1350, 1244, 1128 cm⁻¹; [α]_(D) ²⁴ + 23.6 ± 0.6° (c = 1.014%, MeOH); Anal. (C₂₃H₂₉N₃O₅S.0.4H₂O) Calcd. (%): C, 59.18; H, 6.43; N, 9.00; S, 6.87 Found (%): C, 59.33; H, 6.48; N, 8.87; S, 6.48 Ic-95 mp 118-120° C.; ¹H-NMR (CDCl₃—DMSO—d₆) δ 1.16 (1H, m), 1.26 (3H, t, J = 7.2 Hz), 1.27-1.66 (12H, m), 2.01 (1H, m), 2.59 (1H, m), 3.52 (2H, m), 3.90 (1H, m), 4.00 (2H, s), 4.14 (2H, q, J = 7.2 Hz), 4.48 (2H, br s), 5.62 (1H, br s), 6.68 (1H, br s), 7.38 (1H, br d, J = 8.7 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.96 (1H, s), 8.31 (1H, br s); IR (CHCl₃) 3442, 1724, 1655, 1516, 1477, 1435, 1225, 1217, 1132, 1059 cm⁻¹; [α]_(D) ²³ + 25.9 ± 0.7° (c = 1.012, MeOH) Anal. (C₂₆H₃₄N₂O₆S.0.2H₂O) Calcd. (%): C, 61.69; H, 6.85; N, 5.53; S, 6.33 Found (%): C, 61.71; H, 6.73; N, 5.48; S, 6.32  

TABLE 41 Compound No. Physical property Ic-99 ¹H-NMR (d₆—DMSO) δ 1.19-1.68 (13H, m), 1.93 (1H, br s), 2.43 (1H, br s), 3.41 (2H, t, J = 6.6 Hz), 3.49 (2H, s), 3.71 (1H, m), 3.92 (2H, s), 7.38 (1H, br s), 7.87 (1H, dd, J = 1.8, 8.7 Hz), 8.07 (1H, br s), 8.09 (1H, d, J = 8.4 Hz), 8.35 (1H, d, J = 6.6 Hz), 8.39 (1H, s), 8.85 (1H, d, J = 1.2 Hz); IR (Nujol) 3340, 3251, 2927, 1741, 1655, 1624, 1539, 1458, 1377, 1244, 1134 cm⁻¹; [α]_(D) ²⁵ + 24.2 ± 0.6° (c = 1.009%, MeOH); Anal. (C₂₃H₂₈N₂O₅S.0.5H₂O) Calcd. (%): C, 60.91; H, 6.44; N, 6.18; S, 7.07 Found (%): C, 60.89; H, 6.57; N, 5.80; S, 6.91 Ic-115 mp 133-135° C.; ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.21-1.34 (2H, m), 1.40-1.72 (10H, m), 2.02 (1H, m), 2.47 (3H, s), 2.53 (3H, s), 2.57 (1H, br s), 3.48-3.59 (2H, m), 3.97 (1H, m), 4.03 (2H, s), 6.12 (1H, d, J = 7.5 Hz), 7.05 (1H, s), 7.84 (1H, s), 7.94 (1H, s); IR (Nujol) 3344, 2540, 1730, 1614, 1539, 1219, 1142 cm⁻¹; [α]_(D) ²⁵ + 34.7 ± 0.7° (c = 1.012, MeOH) Anal. (C₂₃H₂₉NO₄S) Calcd. (%): C, 67.10; H, 7.27; N, 3.26; S, 7.64 Found (%): C, 66.81; H, 7.50; N, 3.18; S, 7.32 Ic-128 ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.19-1.68 (12H, m), 1.99 (1H, br s), 2.57 (1H, br s), 3.48 (2H, t, J = 6.3 Hz), 3.49 (2H, s), 3.95 (1H, m), 3.99 (2H, s), 4.85 (2H, br s), 6.27 (1H, d, J = 8.1 Hz), 7.47 (1H, d, J = 9.9 Hz), 7.76 (1H, s), 8.07 (1H, d, J = 8.4 Hz); IR (CHCl₃) 3435, 3192, 2954, 1730, 1637, 1520, 1435, 1275 cm⁻¹; [α]_(D) ²⁶ + 29.9 ± 0.7° (c = 1.011%, MeOH); Anal. (C₂₂H₂₆NO₅SF.0.4H₂O) Calcd. (%): C, 59.20; H, 6.14; N, 3.14; S, 7.18; F, 4.26 Found (%): C, 59.16; H, 5.90; N, 3.05; S, 7.09; F, 4.14 Ic-129 mp 135-137° C.; ¹H-NMR (CDCl₃) δ 1.05 (1H, m), 1.22-1.69 (12H, m), 2.04 (1H, br s), 2.56 (1H, br s), 3.54 (2H, dt, J = 1.5, 6.6 Hz), 3.96 (1H, m), 3.98 (3H, s), 4.03 (2H, s), 6.12 (1H, d, J = 6.9 Hz), 7.52 (1H, d, J = 10.5 Hz), 7.77 (1H, s), 8.04 (1H, d, J = 8.4 Hz); IR (Nujol) 3334, 2924, 1745, 1618, 1535, 1498, 1462, 1415, 1281, 1259 cm⁻¹; [α]_(D) ²⁴ + 23.6 ± 0.6° (c = 1.014%, MeOH); Anal. (C₂₃H₂₈NO₅SF) Calcd. (%): C, 61.45; H, 6.28; N, 3.12; S, 7.13; F, 4.23 Found (%): C, 61.17; H, 6.33; N, 3.03; S, 7.04; F, 4.03 Ic-135 ¹H-NMR (CDCl₃—DMSO—d₆) δ 1.17 (1H, m), 1.26-1.66 (12H, m), 2.00 (1H, m), 2.56 (1H, m), 3.53 (2H, t, J = 6.3 Hz), 3.86 (1H, m), 4.01 (2H, s), 6.62 (1H, br d, J = 8.1 Hz), 7.40 (2H, br s), 7.96 (1H, s), 8.17 (1H, s); IR (nujol) 1726, 1633, 1556, 1303, 1252, 1176, 1130 cm⁻¹; [α]_(D) ²⁴ + 19.5 ± 0.6° (c = 1.009, MeOH) Ic-140 mp 96-98° C.; ¹H-NMR (DMSO—d₆) δ 1.18-1.31 (8H, m), 1.49-1.56 (5H, m), 1.94 (1H, m), 2.38 (1H, br s), 3.40 (2H, t, J = 6.5 Hz), 3.47 (2H, s), 3.68 (1H, m), 3.93 (2H, s), 6.88 (1H, br s), 7.26 (1H, dd, J = 1.5 and 8.7 Hz), 7.50 (1H, br s), 7.54 (1H, d, J = 8.7 Hz), 7.94 (1H, d, J = 1.5 Hz), 8.12 (1H, d, J = 6.6 Hz), 8.59 (1H, s); IR (Nujol) 3386, 3276, 3195, 3064, 2549, 1747, 1697, 1666, 1624, 1560, 1128 cm⁻¹; [α]_(D) ²⁵ + 22.0 ± 0.6° (c = 1.006, MeOH) Anal. (C₂₄H₃₀N₂O₆.0.8H₂O) Calcd. (%): C, 63.09; H, 6.97; N, 6.13 Found (%): C, 63.18; H, 6.98; N, 5.94  

TABLE 42 Compound No. Physical property Ic-142 ¹H-NMR (CDCl₃—CD₃OD) δ 1.19 (1H, m), 1.26-1.31 (2H, m), 1.39- 1.64 (10H, m), 1.98 (1H, m), 2.55 (1H, br s), 3.50 (2H, t, J = 6.3 Hz), 3.86 (1H, m), 4.01 (2H, s), 6.44 (1H, br s), 6.88 (1H, d, J = 7.2 Hz), 7.29 (1H, br s), 7.50 (1H, d, J = 8.4 Hz), 7.89 (1H, dd, J = 1.8 and 8.4 Hz), 8.22 (1H, s), 8.45 (1H, d, J = 1.8 Hz); IR (CHCl₃) 3026, 3014, 2875, 1728, 1662, 1587, 1562, 1510, 1126 cm⁻¹; [α]_(D) ²⁵ + 19.6 ± 0.6° (c = 1.008, MeOH) Anal. (C₂₃H₂₈N₂O₆.0.5H₂O) Calcd. (%): C, 63.14; H, 6.68; N, 6.40 Found (%): C, 63.02; H, 6.49; N, 6.35 Ie-34 ¹H-NMR (CDCl₃) δ 1.08 (1H, m), 1.23-1.71 (12H, m), 2.03 (1H, d, J = 3.3 Hz), 2.60 (1H, br s), 2.63 (2H, t, J = 6.9 Hz), 3.18 (2H, br s), 4.03 (1H, m), 6.45 (1H, d, J = 7.5 Hz), 7.38 (1H, d, J = 5.7 Hz), 7.42 (1H, t, J = 7.5 Hz), 7.58 (1H, d, J = 5.4 Hz), 7.63 (1H, d, J = 6.9 Hz), 7.96 (1H, d, J = 7.8 Hz); IR (CHCl₃) 3452, 2954, 1711, 1649, 1520, 1495, 1458, 1300, 1284 cm⁻¹; [α]_(D) ²⁶ + 38.1 ± 1.6° (c = 0.502%, MeOH); Anal. (C₂₂H₂₇NO₃S₂.0.3H₂O) Calcd. (%): C, 62.47; H, 6.58; N, 3.31; S, 15.16 Found (%): C, 62.53; H, 6.63; N, 3.38; S, 15.16 Ie-49 ¹H-NMR (CDCl₃) δ 1.07 (1H, m), 1.29-1.68 (12H, m), 2.01 (1H, m), 2.55 (1H, m), 2.64 (2H, t, J = 7.5 Hz), 3.18 (2H, s), 3.44 (3H, s), 3.99 (1H, m), 4.78 (2H, s), 6.12 (1H, d, J = 7.2 Hz), 7.33-7.40 (2H, m), 7.79 (1H, dd, J = 6.9, 1.8 Hz), 8.17 (1H, s); IR (CHCl₃) 3440, 2670, 1710, 1650, 1573, 1562, 1509, 1425, 1297, 1238, 1224 cm⁻¹; [α]_(D) ^(24.0) + 33.2 ± 0.7° (c = 1.019, MeOH); Anal. (C₂₄H₃₁NO₅S.0.2H₂O) Calcd. (%): C, 64.18; H, 7.05; N, 3.12 Found (%): C, 64.11; H, 7.11; N, 3.24 IIa-22 ¹H-NMR (CDCl₃) 60.94 (1H, d, J = 10.2 Hz), 1.11 (3H, s), 1.23 (3H, s), 1.34-1.54 (6H, m), 1.65-1.89 (2H, m), 2.00 (1H, m), 2.13-2.39 (5H, m), 4.32 (1H, m), 5.75 (1H, dt, J = 15.9, 1.2 Hz), 6.22 (1H, d, J = 8.7 Hz), 6.98 (1H, dd, J = 2.1, 9.0 Hz), 6.99 (1H, td, J = 7.2, 15.9 Hz), 7.26 (1H, d, J = 2.1 Hz), 7.58 (1H, s), 8.08 (1H, d, J = 9.0 Hz); IR (KBr) 3300, 1695, 1603, 1522, 1468, 1417, 1236 cm⁻¹; [α]_(D) ²⁶ + 31.3 ± 0.7° (c = 1.000, MeOH); Anal. (C₂₅H₃₁NO₄S.0.4H₂O) Calcd. (%): C, 66.91; H, 7.14; N, 3.12; S, 7.14 Found (%): C, 66.81; H, 7.05; N, 3.13; S, 7.07 IIa-23 mp 189-192° C.; ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.25 (3H, s), 1.28-2.39 (14H, m), 4.31 (1H, m), 5.78 (1H, d, J = 15.6 Hz), 6.19 (1H, d, J = 9.6 Hz), 6.99 (1H, m), 7.01 (1H, dd, J = 8.7, 2.7 Hz), 7.66 (1H, d, J = 8.7 Hz), 7.67 (1H, s), 7.89 (1H, d, J = 2.7 Hz); IR (Nujol) 3199, 2683, 1684, 1635, 1599, 1525, 1437, 1304, 1286, 1225 cm⁻¹; [α]_(D) ^(26.0) + 26.8 ± 0.7° (c = 1.011, MeOH); Anal. (C₂₅H₃₁NO₄S.0.3H₂O) Calcd. (%): C, 68.00; H, 7.08; N, 3.17; S, 7.26 Found (%): C, 68.09; H, 6.94; N, 3.16; S, 7.18  

TABLE 43 Compound No. Physical property IIa-24 ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 9.9 Hz), 1.15 (3H, s), 1.27 (3H, s), 1.32-1.60 (6H, m), 1.66-1.90 (2H, m), 2.04 (1H, m), 2.17-2.43 (5H, m), 4.29 (1H, m), 5.79 (1H, d, J = 15.6 Hz), 6.49 (1H, d, J = 9.0 Hz), 6.93 (1H, dd, J = 2.7, 5.7 Hz), 7.02 (1H, td, J = 6.9, 15.6 Hz), 7.31 (1H, d, J = 2.7 Hz), 7.32 (1H, t, J = 5.7 Hz), 7.65 (1H, s), 12.09 (1H, s); IR (CHCl₃) 3521, 3454, 2686, 1695, 1651, 1624, 1585, 1562, 1522, 1456, 1271 cm⁻¹; [α]_(D) ²⁷ + 29.4 ± 0.7° (c = 1.004, MeOH); Anal. (C₂₅H₃₁NO₄S.0.4H₂O) Calcd. (%): C, 66.91; H, 7.14; N, 3.12; S, 7.14 Found (%): C, 66.97; H, 7.01; N, 3.23; S, 7.17 IIa-28 mp 172-174° C.; ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 9.9 Hz), 1.13 (3H, s), 1.25 (3H, s), 1.30-2.42 (14H, m), 4.31 (1H, m), 5.79 (1H, dt, J = 15.6, 1.5 Hz), 6.08 (1H, d, J = 9.3 Hz), 7.03 (1H, dt, J = 15.6, 7.2 Hz), 7.17 (1H, dt, J = 8.7, 2.7 Hz), 7.80 (1H, dd, J = 8.7, 5.1 Hz), 7.83 (1H, s), 8.07 (1H, dd, J = 10.2, 2.7 Hz); IR (Nujol) 3374, 2719, 1698, 1650, 1627, 1525, 1442, 1431 cm⁻¹; [α]_(D) ^(24.0) + 28.2 ± 0.7° (c = 1.012, MeOH); Anal. (C₃₀H₃₇NO₄S.1.1H₂O) Calcd. (%): Calcd. (%): C, 67.57; H, 6.50; N, 3.15; S, 7.22 Found (%): C, 67.35; H, 6.76; N, 3.26; S, 7.12 IIa-34 mp 141-142° C.; ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 9.9 Hz), 1.16 (3H, s), 1.24 (3H, s), 1.29-2.42 (14H, m), 4.39 (1H, m), 5.77 (1H, d, J = 15.6 Hz), 6.43 (1H, d, J = 8.7 Hz), 7.01 (1H, dt, J = 15.6, 3.6 Hz), 7.38 (1H, d, J = 5.4 Hz), 7.43 (1H, t, J = 7.5 Hz), 7.54 (1H, d, J = 7.5 Hz), 7.59 (1H, d, J = 5.4 Hz), 7.96 (1H, d, J = 7.5 Hz); IR (Nujol) 3380, 2686, 1699, 1619, 1581, 1461, 1234, 1200 cm⁻¹; [α]_(D) ^(25.0) + 48.8 ± 0.9° (c = 1.009, MeOH); Anal. (C₂₅H₃₁NO₃S) Calcd. (%): C, 70.55; H, 7.34; N, 3.29; S, 7.53 Found (%): C, 70.35; H, 7.33; N, 3.31; S, 7.44 IIa-51 mp 211-213° C.; ¹H-NMR (CDCl₃—CD₃OD) δ 0.94 (1H, d, J = 9.9 Hz), 1.15 (3H, s), 1.24 (3H, s), 1.36-1.55 (6H, m), 1.70 (1H, m), 1.83 (1H, m), 2.02 (1H, m), 2.15-2.38 (5H, m), 4.29 (1H, m), 5.74 (1H, d, J = 15.6 Hz), 6.90 (1H, dd, J = 2.1, 8.7 Hz), 6.90 (1H, dt, J = 15.6, 6.9 Hz), 7.00 (1H, d, J = 2.1 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.99 (1H, s); IR (KBr) 3425, 3255, 2600, 1938, 1685, 1626, 1605, 1579, 1522, 1442, 1265, 1146, 1128, 1107 cm⁻¹; [α]_(D) ²⁷ + 23.9 ± 0.6° (c = 1.004, MeOH); Anal. (C₂₅H₃₁NO₅.0.1H₂O) CaLcd. (%): C, 70.27; H, 7.36; N, 3.28 Found (%): C, 70.13; H, 7.34; N, 3.47 IIa-52 mp 159-160° C.; ¹H-NMR (CDCl₃) δ 0.92 (1H, d, J = 9.9 Hz), 1.11 (3H, s), 1.21 (3H, s), 1.36-1.50 (6H, m), 1.63 (1H, m), 1.79 (1H, m), 1.98 (1H, s), 2.10-2.20 (4H, m), 2.30 (1H, s), 4.30 (1H, s), 5.69 (1H, d, J = 15.6 Hz), 6.20 (1H, d, J = 9.0 Hz), 6.91 (1H, dd, J = 2.4, 9.0 Hz), 6.94 (1H, dt, J = 15.6, 6.9 Hz), 7.33 (1H, d, J = 9.0 Hz), 7.56 (1H, d, J = 2.4 Hz), 7.98 (1H, s); IR (KBr) 3255, 2688, 1684, 1643, 1560, 1522, 1306, 1288, 1269, 1219, 1192, 1167, 1134 cm⁻¹; [α]_(D) ²⁵ + 21.8 ± 0.6° (c = 1.020, MeOH); Anal. (C₂₅H₃₁NO₅) Calcd. (%): C, 70.57; H, 7.34; N, 3.29 Found (%): C, 70.41; H, 7.16; N, 3.34  

TABLE 44 Compound No. Physical property IIa-54 ¹H-NMR (CDCl₃) δ 0.95 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H, s), 1.32-1.57 (6H, m), 1.69-1.88 (2H, m), 2.02 (1H, m), 2.16-2.24 (4H, m), 2.35 (1H, m), 4.32 (1H, m), 5.78 (1H, dt, J = 15.3, 1.5 Hz), 6.02 (1H, d, J = 9.0 Hz), 7.02 (1H, dt, J = 15.3, 6.9 Hz), 7.09-7.15 (1H, m), 7.26 (1H, dd, J = 8.7, 2.1 Hz), 7.82 (1H, dd, J = 8.7, 5.4 Hz), 8.05 (1H, s); IR (CHCl₃) 3446, 2680, 1695, 1652, 1257, 1220, 1214 cm⁻¹; [α]_(D) ^(25.0) + 23.3 ± 0.6° (c = 1.008, MeOH); Anal. (C₂₅H₃₀FNO₄.0.4H₂O) Calcd. (%): C, 69.07; H, 7.14; F, 4.37; N, 3.22 Found (%): C, 68.82; H, 6.89; F, 4.49; N, 3.34 IIa-66 ¹H-NMR (CDCl3) δ 0.95 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H, s), 1.40-1.55 (6H, m), 1.70-1.85 (2H, m), 2.00 (1H, br s), 2.12-2.37 (5H, m), 4.30 (1H, m), 5.80 (1H, d, J = 15.6 Hz), 6.17 (1H, d, J = 9.0 Hz), 6.68 (1H, d, J = 2.1 Hz), 6.88 (1H, d, J = 5.4 Hz), 6.94 (1H, d, J = 5.4 Hz), 7.03 (1H, dt, J = 15.6 and 6.9 Hz), 11.22 (1H, s); IR (CHCl₃) 3448, 3188, 1693, 1637, 1543, 1518, 1471, 1421, 1396, 1385, 1257, 1232 cm⁻¹; [α]_(D) ²⁶ + 18.2 ± 0.6° (c = 1.005, MeOH) Anal. (C₂₃H₃₀N₂O₃S.0.2H₂O) Calcd. (%): C, 66.06; H, 7.33; N, 6.70; S, 7.66 Found (%): C, 66.19; H, 7.06; N, 6.83; S, 7.35 IIa-81 mp 167-168° C.; ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.23 (3H, s), 1.33-1.54 (6H, m), 1.64 (1H, m), 1.80 (1H, m), 1.99 (1H, br s), 2.12-2.38 (5H, m), 2.44 (3H, s), 4.31 (1H, m), 5.71 (1H, d, J = 15.6 Hz), 6.08 (1H, d, J = 9.6 Hz), 6.72 (1H, d, J = 2.1 Hz), 6.97 (1H, dt, J = 15.6 and 6.9 Hz), 7.30 (1H, d, J = 2.1 Hz), 7.97 (1H, s); IR (KBr) 3276, 2686, 1693, 1643, 1610, 1562, 1518, 1460, 1417, 1385, 1367, 1284, 1200, 1136 cm⁻¹; [α]_(D) ²⁴ + 23.0 ± 0.6° (c = 1.020, MeOH) Anal. (C₂₆H₃₃NO₅.0.2HO) Calcd. (%): C, 70.47; H, 7.60; N, 3.16 Found (%): C, 70.50; H, 7.47; N, 3.35 IIa-94 ¹H-NMR (CDCl₃) δ 0.97 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.25 (3H, s), 1.42-1.56 (6H, m), 1.70-1.88 (2H, m), 2.00 (1H, m), 2.03 (3H, s), 2.18-2.38 (5H, m), 4.31 (1H, m), 4.55 (2H, m), 5.78 (1H, d, J = 15.6 Hz), 6.18-6.23 (2H, m), 6.98 (1H, dt, J = 15.6, 6.9 Hz), 7.34 (1H, dd, J = 1.8, 8.4 Hz), 7.77 (1H, s), 7.79 (1H, d, J = 8.4 Hz), 8.31 (1H, br s); IR (CHCl₃) 3446, 1695, 1655, 1514, 1471, 1435, 1369, 1222, 1215 cm⁻¹; [α]_(D) ²⁴ + 23.4 ± 0.6° (c = 1.006, MeOH) Anal. (C₂₈H₃₆N₂O₄S.0.4H₂O) Calcd. (%): C, 66.74; H, 7.36; N, 5.56; S, 6.36 Found (%): C, 66.79; H, 7.23; N, 5.51; S, 6.39 IIa-99 mp 130-133° C.; 0.85 (1H, d, J = 9.6 Hz), 1.12 and 1.19 (3H, s), 1.25-2.38 (12H, m), 3.99 (1H, m), 5.72 (1H, d, J = 15.6 Hz), 6.79 (1H, dt, J = 6.6, 15.6 Hz), 7.38 (1H, s), 7.87 (1H, dd, J = 1.8, 8.7 Hz), 8.05-8.13 (3H, m), 8.31 (1H, s), 8.82 (1H, d, J = 1.2 Hz); IR (Nujol) 3375, 3178, 2918, 1703, 1653, 1626, 1527, 1460, 1398, 1255 cm⁻¹; [α]_(D) ²⁵ + 27.9 ± 0.7° (c = 1.011%, MeOH); Anal. (C₂₆H₃₂N₂O₄S.0.7AcOEt) Calcd. (%): C, 65.23; H, 7.15; N, 5.28; S, 6.05 Found (%): C, 64.99; H, 6.91; N, 5.52; S, 6.18  

TABLE 45 Compound No. Physical property IIb-28 ¹H-NMR (CDCl₃) δ 0.97 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.26 (3H, s), 1.59 (1H, ddd, J = 2.7, 5.7, 13.5 Hz), 1.95-2.57 (7H, m), 4.06- 4.27 (4H, m), 4.33 (1H, m), 5.60-5.80 (2H, m), 6.18 (1H, d, J = 9.0 Hz), 7.17 (1H, dt, J = 3.0, 9.0 Hz), 7.79 (1H, dd, J = 4.8, 8.7 Hz), 7.89 (1H, s), 8.04 (1H, dd, J = 2.7, 9.9 Hz); IR (CHCl₃) 3442, 3022, 1734, 1651, 1603, 1564, 1516, 1496, 1471, 1433, 1244, 1119 cm⁻¹; [α]_(D) ²⁵ + 43.8 ± 1.4° (c = 1.003%, MeOH); Anal. (C₂₄H₂₈NO₄SF.0.4H₂O) Calcd. (%): C, 63.67; H, 6.41; F, 4.20; N, 3.09; S, 7.08 Found (%): C, 63.73; H, 6.35; F, 4.11; N, 3.20; S, 7.07 IIc-04 mp 132-134° C.; ¹H-NMR (CDCl₃) δ 0.94 (1H, d, J = 9.9 Hz), 1.13 (3H, s), 1.23 (3H, s), 1.40-1.86 (8H, m), 2.00 (1H, m), 2.13 (1H, m), 2.18-2.37 (2H, m), 3.53 (2H, t, J = 6.0 Hz), 4.04 (2H, s), 4.28 (1H, m), 6.14 (1H, d, J = 9.0 Hz), 7.31-7.36 (2H, m), 7.85 (1H, m); IR (Nujol) 3373, 3105, 2528, 1736, 1601, 1556, 1215, 1138 cm⁻¹; [α]_(D) ²⁵ + 22.7 ± 0.6° (c = 1.004, MeOH); Anal. (C₂₀H₂₉NO₄S) Calcd. (%): C, 63.30; H, 7.70; N, 3.69; S, 8.45 Found (%): C, 63.10; H, 7.73; N, 3.74; S, 8.34 IIc-17 mp 125-126° C.; ¹H-NMR (CDCl₃) δ 0.97 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.25 (3H, s), 1.40-1.93 (8H, m), 2.02 (1H, m), 2.17-2.41 (3H, m), 3.53 (2H, t, J = 6.3 Hz), 4.02 (2H, s), 4.36 (1H, m), 6.21 (1H, d, J = 9.0 Hz), 7.37-7.49 (2H, m), 7.84 (1H, s), 7.87 (1H, m), 8.30 (1H, m); IR (Nujol) 3282, 2540, 1724, 1604, 1554, 1246, 1228, 1130, 1109 cm⁻¹; [α]_(D) ²⁵ + 29.6 ± 0.7° (c = 1.013, MeOH); Anal. (C₂₄H₃₁NO₄S) Calcd. (%): C, 67.10; H, 7.27; N, 3.26; S, 7.46 Found (%): C, 66.88; H, 7.10; N, 3.30; S, 7.25 IIc-19 ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.24 (3H, s), 1.40-1.92 (8H, m), 2.01 (1H, m), 2.17-2.40 (3H, m), 2.48 (3H, s), 3.47-3.58 (2H, m), 3.97 (1H, m), 4.02 (2H, s), 4.34 (1H, m), 6.21 (1H, d, J = 9.3 Hz), 7.28 (1H, m), 7.65 (1H, m), 7.75 (1H, s), 8.16 (1H, d, J = 8.4 Hz); IR (CHCl₃) 3442, 2567, 1780, 1732, 1649, 1514, 1242, 1134 cm⁻¹; [α]_(D) ²⁵ + 28.7 ± 0.8° (c = 1.003, MeOH) Anal. (C₂₅H₃₃NO₄S.0.4H₂O) Calcd. (%): C, 66.61; H, 7.56; N, 3.11; S, 7.11 Found (%): C, 66.67; H, 7.37; N, 3.03; S, 6.88 IIc-20 mp 87-90° C.; ¹H-NMR (CDCl₃) δ 0.97 (1H, d, J = 10.5 Hz), 1.14 (3H, s), 1.26 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.41 (3H, m), 2.49 (3H, s), 3.54 (2H, t, J = 6.0 Hz), 4.02 (2H, s), 4.35 (1H, m), 6.20 (1H, d, J = 8.4 Hz), 7.23 (1H, dd, J = 0.6, 8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.80 (1H, s), 8.11 (1H, d, J = 0.6 Hz); IR (Nujol) 3411, 3357, 1736, 1604, 1531, 1219, 1134 cm⁻¹; [α]_(D) ²⁵ + 27.4 ± 0.7° (c = 1.013, MeOH); Anal. (C₂₅H₃₃NO₄S.0.3H₂O) Calcd. (%): C, 66.87; H, 7.54; N, 3.12; S, 7.14 Found (%): C, 66.90; H, 7.50; N, 3.23; S, 7.05  

TABLE 46 Compound No. Physical property IIc-21 mp 183-185° C.; ¹H-NMR (d₆—DMSO) δ 0.84 (1H, d, J = 9.6 Hz), 1.11 (3H, s), 1.18 (3H, s), 1.22-1.60 (7H, m), 1.93 (1H, m), 2.10-2.34 (6H, m), 3.41 (2H, t, J = 6.3 Hz), 3.92 (2H, s), 3.97 (1H, m), 6.79 (1H, d, J = 7.8 Hz), 7.24 (1H, t, J = 7.8 Hz), 7.77 (1H, d, J = 7.8 Hz), 7.97 (1H, d, J = 6.9 Hz), 8.18 (1H, s), 10.39 (1H, br), 12.53 (1H, br); IR (Nujol) 3425, 3303, 3093, 2598, 1729, 1604, 1574, 1522, 1469, 1282, 1230, 1122 cm⁻¹; [α]_(D) ²⁷ + 32.1 ± 0.7° (c = 1.000, MeOH); Anal. (C₂₄H₃₁NO₅S.0.4H₂O) Calcd. (%): C, 63.66; H, 7.08; N, 3.09; S, 7.08 Found (%): C, 63.79; H, 7.14; N, 3.15; S, 7.06 IIc-22 ¹H-NMR (CDCl₃) δ 0.93 (1H, d, J = 10.2 Hz), 1.10 (3H, s), 1.23 (3H, s), 1.38-1.92 (8H, m), 1.99 (1H, m), 2.16-2.38 (3H, m), 3.46 (2H, t, J = 6.3 Hz), 3.95 (2H, s), 4.32 (1H, m), 6.32 (1H, d, J = 9.0 Hz), 6.96 (1H, dd, J = 2.1, 9.0 Hz), 7.24 (1H, t, J = 2.1 Hz), 7.51 (1H, s), 8.04 (1H, d, J = 9.0 Hz); IR (KBr) 3359, 1734, 1603, 1523, 1469, 1236, 1128 cm⁻¹; [α]_(D) ²⁶ + 26.8 ± 0.7° (c = 1.015, MeOH); Anal. (C₂₄H₃₁NO₅S.0.4H₂O) Calcd. (%): C, 63.66; H, 7.08; N, 3.09; S, 7.08 Found (%): C, 63.64; H, 7.13; N, 3.07; S, 6.99 IIc-23 ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 10.5 Hz), 1.12 (3H, s), 1.24 (3H, s), 1.38-2.40 (12H, m), 3.47 (2H, t, J = 6.6 Hz), 3.97 (2H, s), 4.33 (1H, m), 5.36 (2H, br s), 6.28 (1H, d, J = 9.0 Hz), 7.00 (1H, dd, J = 2.1, 8.7 Hz), 7.65 (1H, d, J = 8.7 Hz), 7.71 (1H, s), 7.98 (1H, d, J = 2.1 Hz); IR (CHCl₃) 3438, 3238, 1730, 1637, 1601, 1518, 1436, 1124 cm⁻¹; [α]_(D) ²⁴ + 23.7 ± 0.6° (c = 1.004, MeOH); Anal. (C₂₄H₃₁NO₅S.0.5H₂O) Calcd. (%): C, 63.41; H, 7.10; N, 3.08; S, 7.05 Found (%): C, 63.40; H, 6.98; N, 3.25; S, 7.09 IIc-24 ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.5 Hz), 1.16 (3H, s), 1.20 (3H, s), 1.40-1.92 (8H, m), 2.04 (1H, m), 2.18-2.42 (3H, m), 3.55 (2H, t, J = 6.3 Hz), 4.04 (2H, s), 4.30 (1H, m), 6.55 (1H, d, J = 8.7 Hz), 6.93 (1H, dd, J = 2.4, 6.6 Hz), 7.32 (1H, d, J = 2.4 Hz), 7.33 (1H, d, J = 6.6 Hz), 7.67 (1H, s), 12.10 (1H, s); IR (CHCl₃) 3508, 3450, 2684, 1780, 1732, 1624, 1585, 1562, 1523, 1456, 1269 cm⁻¹; [α]_(D) ²⁷ + 28.4 ± 0.7° (c = 1.000, MeOH); Anal. (C₂₄H₃₁NO₅S.0.5H₂O) Calcd. (%): C, 63.41; H, 7.10; N, 3.08; S, 7.05 Found (%): C, 63.48; H, 6.98; N, 3.16; S, 6.98 IIc-27 ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.25 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.17-2.41 (3H, m), 3.53 (2H, t, J = 6.6 Hz), 4.03 (2H, s), 4.32 (1H, m), 6.18 (1H, d, J = 8.7 Hz), 7.21 (1H, dt, J = 2.4, 9.0 Hz), 7.53 (1H, dd, J = 2.4, 8.4 Hz), 8.33 (1H, dd, J = 5.1, 9.0 Hz); IR (CHCl₃) 3508, 3442, 1780, 1732, 1651, 1603, 1516, 1468, 1244, 1122 cm⁻¹; [α]_(D) ²⁵ + 29.2 ± 0.7° (c = 1.006, MeOH); Anal. (C₂₄H₃₀FNO₄S.0.3H₂O) Calcd. (%): C, 63.64; H, 6.81; F, 4.19; N, 3.09; S, 7.08 Found (%): C, 63.65; H, 6.76; F, 4.10; N, 3.14; S, 7.16  

TABLE 47 Compound No. Physical property IIc-28 mp 144-146° C.; ¹H-NMR (CDCl₃) δ 0.97 (1H, d, J = 10.5 Hz), 1.13 (3H, s), 1.25 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.17-2.41 (3H, m), 3.52-3.57 (2H, m), 4.03 (2H, s), 4.33 (1H, m), 6.16 (1H, d, J = 8.4 Hz), 7.17 (1H, dt, J = 2.7, 8.7 Hz), 7.78 (1H, dd, J = 5.1, 8.7 Hz), 8.06 (1H, dd, J = 2.7, 9.9 Hz); IR (Nujol) 3286, 2538, 1722, 1608, 1552, 1244, 1136 cm⁻¹; [α]_(D) ²⁵ + 27.3 ± 0.7° (c = 1.009, MeOH); Anal. (C₂₄H₃₀FNO₄S) Calcd. (%): C, 64.41; H, 6.76; F, 4.24; N, 3.13; S, 7.16 Found (%): C, 64.23; H, 6.84; F, 4.16; N, 3.19; S, 7.12 IIc-34 mp 95-96° C.; ¹H-NMR (CDCl₃) δ 0.97 (1H, d, J = 10.5 Hz), 1.17 (3H, s), 1.24 (3H, s), 1.40-1.96 (8H, m), 2.02 (1H, m), 2.18-2.41 (3H, m), 3.47-3.58 (2H, m), 4.01 (2H, s), 4.40 (1H, m), 6.50 (1H, d, J = 8.7 Hz), 7.38 (1H, d, J = 5.7 Hz), 7.43 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 7.8 Hz), 7.59 (1H, d, J = 5.7 Hz), 7.96 (1H, dd, J = 1.2, 7.8 Hz); IR (Nujol) 3265, 2544, 1728, 1608, 1577, 1550, 1319, 1240, 1225, 1128, 1111 cm⁻¹; [α]_(D) ²⁵ + 45.6 ± 0.9° (c = 1.006, MeOH); Anal. (C₂₄H₃₁NO₄S) Calcd. (%): C, 67.10; H, 7.27; N, 3.26; S, 7.46 Found (%): C, 66.88; H, 7.14; N, 3.34; S, 7.43 IIc-39 ¹H-NMR (CDCl₃) δ 0.99 (1H, d, J = 10.2 Hz), 1.17 (3H, s), 1.24 (3H, s), 1.44-1.94 (8H, m), 2.02 (1H, m), 2.18-2.40 (3H, m), 3.53 (2H, t, d = 6.3 Hz), 3.98 (3H, s), 4.01 (2H, s), 4.40 (1H, m), 6.43 (1H, s), 6.49 (1H, d, J = 8.7 Hz), 7.42 (1H, t, J = 7.5 Hz), 7.58 (1H, dd, J = 0.9, 7.5 Hz), 7.93 (1H, dd, J = 0.9, 7.5 Hz); IR (CHCl₃) 3455, 1780, 1732, 1649, 1508, 1373, 1205, 1151 cm⁻¹; [α]_(D) ²⁴ + 41.7 ± 0.8° (c = 1.007, MeOH); Anal. (C₂₅H₃₃NO₅S.0.2H₂O) Calcd. (%): C, 64.82; H, 7.27; N, 3.02; S, 6.92 Found (%): C, 64.85; H, 7.30; N, 3.10; S, 6.64 IIc-41 ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 9.9 Hz), 1.19 (3H, s), 1.25 (3H, s), 1.46-1.96 (8H, m), 2.03 (1H, m), 2.22-2.41 (3H, m), 3.53 (2H, t, J = 6.3 Hz), 4.00 (2H, s), 4.43 (1H, m), 6.53 (1H, d, J = 9.3 Hz), 7.44-7.56 (3H, m), 7.66 (1H, d, J = 6.3 Hz), 7.91 (1H, m), 8.18 (1H, m), 8.30 (1H, d, J = 7.5 Hz); IR (CHCl₃) 3454, 1780, 1731, 1649, 1512, 1444, 1217, 1122 cm⁻¹; [α]_(D) ²⁵ + 45.4 ± 0.8° (c = 1.013, MeOH); Anal. (C₂₈H₃₃NO₄S.0.3H₂O) Calcd. (%): C, 69.34; H, 6.98; N, 2.89; S, 6.61 Found (%): C, 69.21; H, 7.01; N, 3.04; S, 6.59 IIc-49 ¹H-NMR (CDCl₃) δ 0.97 (1H, d, J = 9.9 Hz), 1.17 (3H, s), 1.25 (3H, s), 1.49-2.39 (12H, m), 3.45 (2H, s), 3.51 (2H, t, J = 6.3 Hz), 4.00 (3H, s), 4.37 (1H, m), 4.79 (2H, s), 6.20 (1H, d, J = 9.3 Hz), 7.32- 7.40 (2H, m), 7.74 (1H, dd, J = 7.2, 1.5 Hz), 8.16 (1H, s); IR (CHCl₃) 3444, 2829, 1733, 1650, 1573, 1508, 1471, 1425, 1384, 1367, 1214 cm⁻¹; [α]_(D) ^(24.0) + 24.8 ± 0.6° (c = 1.020, MeOH); Anal. (C₂₆H₃₅NO₆.0.5H₂O) Calcd. (%): C, 66.93; H, 7.78; N, 3.00 Found (%): C, 66.85; H, 7.78; N, 3.10  

TABLE 48 Compound No. Physical property IIc-51 ¹H-NMR (CDCl₃) δ 0.93 (1H, d, J = 9.9 Hz), 1.14 (3H, s), 1.23 (3H, s), 1.41-1.90 (8H, m), 2.00 (1H, m), 2.17-2.38 (3H, m), 3.49 (2H, t, J = 6.3 Hz), 3.99 (2H, s), 4.29 (1H, m), 6.27 (1H, d, J = 9.0 Hz), 6.89 (1H, dd, J = 2.1, 8.7 Hz), 6.99 (1H, d, J = 2.1 Hz), 7.56 (1H, d, J = 8.7 Hz), 8.00 (1H, s); IR (KBr) 3475, 1734, 1626, 1560, 1518, 1493, 1471, 1441, 1385, 1367, 1265, 1221, 1122 cm⁻¹; [α]_(D) ²⁷ + 22.3 ± 0.6° (c = 1.000, MeOH); Anal. (C₂₄H₃₁NO₆.0.5H₂O) Calcd. (%): C, 65.74; H, 7.35; N, 3.19 Found (%): C, 65.79; H, 7.43; N, 3.36 IIc-52 ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 10.5 Hz), 1.13 (3H, s), 1.24 (3H, s), 1.48-1.90 (8H, m), 2.01 (1H, m), 2.18-2.40 (3H, m), 3.49 (2H, t, J = 6.5 Hz), 3.95 (1H, d, J = 16.5 Hz), 4.02 (1H, d, J = 16.5 Hz), 4.32 (1H, m), 6.12 (1H, d, J = 9.0 Hz), 6.91 (1H, dd, J = 2.7, 9.0 Hz), 7.36 (1H, d, J = 9.0 Hz), 7.52 (1H, d, J = 9.0 Hz), 7.98 (1H, s); IR (CHCl₃) 3442, 3265, 1730, 1643, 1620, 1558, 1514, 1468, 1385, 1367, 1190, 1167, 1136 cm⁻¹; [α]_(D) ²⁷ + 21.6 ± 0.6° (c = 1.006, MeOH); Anal. (C₂₄H₃₁NO₆0.5H₂O) Calcd. (%): C, 65.74; H, 7.35; N, 3.19 Found (%): C, 65.80; H, 7.46; N, 3.34 IIc-56 ¹H-NMR (CDCl₃) δ 0.99 (1H, d, J = 10.2 Hz), 1.25 (6H, s), 1.47-1.79 (7H, m), 1.92-2.05 (2H, m), 2.19 (1H, m), 2.25-2.39 (2H, m), 3.51 (2H, t, J = 6.3 Hz), 3.96 (1H, d, J = 16.2 Hz), 4.00 (1H, d, J = 16.2 Hz), 4.46 (1H, m), 6.89 (1H, d, J = 2.1 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.69 (1H, d, J = 2.1 Hz), 7.74 (1H, dd, J = 1.2, 7.8 Hz), 7.88 (1H, d, J = 9.3 Hz), 8.13 (1H, dd, J = 1.2, 7.8 Hz); IR (CHCl₃) 3435, 2665, 2573, 2474, 1780, 1732, 1651, 1606, 1595, 1547, 1535, 1473, 1421, 1367, 1352, 1325, 1296, 1167, 1120 cm⁻¹; [α]_(D) ^(25.5) + 14.7 ± 0.5° (c = 1.007, MeOH); Anal. (C₂₄H₃₁NO₅.0.3H₂O) Calcd. (%): C, 68.81; H, 7.60; N, 3.34 Found (%): C, 68.71; H, 7.60; N, 3.44 IIc-65 mp 191-192° C.; ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.5 Hz), 1.15 (3H, s), 1.25 (3H, s), 1.46-1.88 (8H, m), 2.01 (1H, m), 2.11 (1H, m), 2.21-2.37 (2H, m), 3.51-3.58 (2H, m), 4.07 (2H, s), 4.30 (1H, m), 6.21 (1H, d, J = 9.3 Hz), 6.68 (1H, d, J = 1.2 Hz), 6.99 (1H, d, J = 5.4 Hz), 7.23 (1H, dd, J = 0.6, 5.4 Hz), 11.27 (1H, s) ; IR (KBr) 3433, 3276, 2663, 2534, 1736, 1591, 1541, 1508, 1473, 1458, 1244, 1228, 1211, 1151 cm⁻¹; [α]_(D) ²⁵ + 18.0 ± 06° (c = 1.008, MeOH); Anal. (C₂₂H₃₀N₂O₄S.0.1H₂O) Calcd. (%): C, 62.86; H, 7.24; N, 6.66; S, 7.63 Found (%): C, 62.81; H, 7.30; N, 6.80; S, 7.47 IIc-66 ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H, s), 1.46-1.88 (8H, m), 2.01 (1H, m), 2.14 (1H, m), 2.21-2.37 (2H, m), 3.53 (2H, t, J = 6.6 Hz), 4.07 (2H, s), 4.29 (1H, m), 6.20 (1H, d, J = 9.3 Hz), 6.64 (1H, d, J = 2.1 Hz), 6.86 (1H, d, J = 5.4 Hz), 6.92 (1H, d, J = 5.4 Hz), 11.06 (1H, s); IR (CHCl₃) 3448, 3209, 1726, 1631, 1543, 1518, 1126 cm⁻¹; [α]_(D) ²⁵ + 14.4 ± 0.5° (c = 1.007, MeOH); Anal. (C₂₂H₃₀N₂O₄S.0.4H₂O) Calcd. (%): C, 62.06; H, 7.29; N, 6.58; S, 7.53 Found (%): C, 62.02; H, 7.31; N, 6.67; S, 7.56  

TABLE 49 Compound No. Physical property IIc-81 ¹H-NMR (CDCl₃) δ 0.92 (1H, d, J = 10.2 Hz), 1.09 (3H, s), 1.20 (3H, s), 1.41-1.73 (7H, m), 1.82 (1H, m), 1.96 (1H, br s), 2.14-2.35 (3H, m), 2.41 (3H, s), 3.46 (2H, t, J = 6.3 Hz), 3.98 (2H, s), 4.27 (1H, m), 6.22 (1H, d, J = 9.0 Hz), 6.72 (1H, d, J = 2.1 Hz), 7.24 (1H, d, J = 2.1 Hz), 8.03 (1H, s); IR (CHCl₃) 3599, 3442, 3265, 2565, 1730, 1645, 1608, 1570, 1514, 1460, 1417, 1385, 1367, 1329, 1286, 1240, 1137 cm⁻¹; [α]_(D) ²⁴ + 24.2 ± 0.6° (c = 1.014, MeOH) Anal. (C₂₅H₃₃NO₆.O.4H₂O) Calcd. (%): C, 66.62; H, 7.55; N, 3.10 Found (%): C, 66.66; H, 7.47; N, 3.29 IIc-84 ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 10.2 Hz), 1.12 (3H, s), 1.25 (3H, s), 1.34 (2H, t, J = 7.5 Hz), 1.44-2.41 (10H, m), 3.56 (2H, br t, J = 5.4 Hz), 4.04 (2H, br s), 4.22-4.40 (3H, m), 6.22 (1H, d, J = 9.0 Hz), 7.65 (1H, dd, J = 1.5, 8.7 Hz), 7.77 (1H, d, J = 8.7 Hz), 7.78 (1H, br s), 8.22 (1H, br s); IR (CHCl₃) 3437, 2924, 1730, 1651, 1514, 1441, 1319 cm⁻¹; [α]_(D) ²⁴ + 20.9 ± 0.6° (c = 1.010%, MeOH); Anal. (C₂₇H₃₆N₂O₆S.0.4H₂O) Calcd. (%): C, 61.90; H, 7.08; N, 5.35; S, 6.12 Found (%): C, 61.82; H, 6.85; N, 5.30; S, 6.09 IIc-86 ¹H-NMR (d₆—DMSO) δ 0.85 (1H, d, J = 8.7 Hz), 1.11 (3H, s), 1.18 (3H, s), 1.27-2.38 (12H, m), 3.41 (2H, t, J = 6.3 Hz), 3.73 (2H, s), 3.97 (1H, m), 5.83 (2H, br s), 7.61 (1H, dd, J = 2.1, 8.7 Hz), 7.83 (1H, d, J = 8.7 Hz), 7.98 (1H, d, J = 6.6 Hz), 8.18 (1H, br s), 8.28 (1H, d, J = 2.1 Hz), 8.73 (1H, s), 12.54 (1H, br s); IR (Nujol) 3334 2923, 1676, 1633, 1571, 1523, 1442, 1377, 1244, 1126 cm⁻¹; [α]_(D) ²⁴ + 19.1 ± 0.6° (c = 1.018%, MeOH); Anal. (C₂₅H₃₃N₃O₅S.0.4H₂O) Calcd. (%): C, 60.68; H, 6.88; N, 8.49; S, 6.48 Found (%): C, 60.73; H, 6.86; N, 8.67; S, 6.41 IIc-94 ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 10.2 Hz), 1.15 (3H, s), 1.26 (3H, s), 1.48-1.91 (8H, m), 2.02 (1H, m), 2.06 (3H, s), 2.18-2.40 (3H, m), 3.51 (2H, t, J = 6.3 Hz), 3.90 and 3.97 (each 1H, ABq, J = 16.2 Hz), 4.36 (1H, m), 4.49 (1H, dd, J = 6.3, 15.0 Hz), 4.61 (1H, dd, J = 6.3, 15.0 Hz), 6.27 (1H, br d, J = 9.0 Hz), 6.41 (1H, br s), 7.33 (1H, br d, J = 8.7 Hz), 7.76 (1H, s), 7.79 (1H, d, J = 8.7 Hz), 8.29 (1H, br s); IR (CHCl₃) 3444, 1733, 1653, 1516, 1471, 1435, 1367, 1240, 1130 cm⁻¹; [α]_(D) ²⁴ + 23.2 ± 0.6° (c = 1.015, MeOH) Anal. (C₂₇H₃₆N₂O₅S.0.3H₂O) Calcd. (%): C, 64.08; H, 7.29; N, 5.54; S, 6.34 Found (%): C, 63.99; H, 7.24; N, 5.46; S, 6.35 IIc-95 mp 133-134° C.; ¹H-NMR (CDCl₃—DMSO—d₆) δ 0.96 (1H, d, J = 9.9 Hz), 1.13 (3H, s), 1.25 (3H, s), 1.26 (3H, t, J = 7.5 Hz), 1.42-2.03 (9H, m), 2.22-2.39 (3H, m), 3.52 (2H, t, J = 6.6 Hz), 3.99 (2H, s), 4.14 (2H, q, J = 7.5 Hz), 4.29 (1H, m), 4.49 (2H, br s), 5.50 (1H, br s), 6.34 (1H, br d, J = 8.7 Hz), 7.38 (1H, d, J = 8.1 Hz), 7.82 (1H, d, J = 8.1 Hz), 7.84 (1H, br s), 8.30 (1H, s); IR (CHCl₃) 3446, 1722, 1653, 1514, 1471, 1435, 1385, 1238, 1132, 1061 cm⁻¹; [α]_(D) ²³ + 22.9 ± 0.6° (c = 1.013, MeOH) Anal. (C₂₈H₃₈N₂O₆S) Calcd. (%): C, 63.37; H, 7.22; N, 5.28; S, 6.04 Found (%): C, 63.18; H, 7.14; N, 5.23; S, 5.95  

TABLE 50 Compound No. Physical property IIc-96 ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 10.5 Hz), 1.16 (3H, s), 1.26 (3H, s), 1.47-1.72 (7H, m), 1.86 (1H, m), 2.02 (1H, m), 2.18-2.39 (3H, m), 2.92 (3H, s), 3.51 (2H, m), 3.96 and 4.03 (each 1H, ABq, J = 16.5 Hz), 4.36 (1H, m), 4.44 (2H, br s), 5.75 (1H, br s), 6.24 (1H, br d, J = 8.7 Hz), 7.41 (1H, br d, J = 8.1 Hz), 7.76 (1H, s), 7.83 (1H, d, J = 8.1 Hz), 8.42 (1H, br s); IR (CHCl₃) 3442, 1734, 1649, 1516, 1496, 1471, 1437, 1327, 1223, 1149, 1074 cm⁻¹; [α]_(D) ²⁶ + 19.2 ± 0.6° (c = 1.010, MeOH) Anal. (C₂₆H₃₆N₂O₆S₂.0.4H₂O) Calcd. (%): C, 57.41; H, 6.82; N, 5.15; S, 11.79 Found (%): C, 57.36; H, 6.65; N, 5.02; S, 11.65 IIc-97 ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.2 Hz), 1.13 (3H, s), 1.24 (3H, s), 1.48-1.72 (7H, m), 1.89 (1H, m), 2.00 (1H, m), 2.16-2.38 (3H, m), 3.49 (2H, t, J = 6.6 Hz), 3.89 and 3.96 (each 1H, ABq, J = 16.5 Hz), 4.25 (1H, br d, J = 15.0 Hz), 4.32 (1H, m), 4.46 (1H, br d, J = 15.0 Hz), 6.37 (1H, d, J = 8.4 Hz), 7.21 (1H, dd, J = 1.2, 8.7 Hz), 7.71 (1H, d, J = 8.7 Hz), 7.74 (1H, s), 8.21 (1H, br s); IR (CHCl₃) 3440, 1720, 1645, 1601, 1518, 1471, 1437, 1240, 1215, 1132 cm⁻¹; [α]_(D) ²⁵ + 23.7 ± 0.6° (c = 1.009, MeOH) Anal. (C₂₆H₃₅N₃O₅S.0.5H₂O) Calcd. (%): C, 61.15; H, 7.11; N, 8.23; S, 6.28 Found (%): C, 61.02; H, 6.81; N, 8.14; S, 6.30 IIc-99 mp 164-166° C.; ¹H-NMR (d₆—DMSO) δ 0.85 (1H, d, J = 9.6 Hz), 1.12 (3H, s), 1.19 (3H, s), 1.24-2.37 (12H, m), 3.41 (2H, t, J = 6.3 Hz), 3.92 (2H, s), 3.99 (1H, m), 7.38 (1H, br s), 7.87 (1H, dd, J = 2.1, 8.7 Hz), 8.05-8.13 (3H, m), 8.32 (1H, s), 8.82 (1H, d, J = 1.2 Hz); IR (Nujol) 3448, 3356, 3211, 2925, 1718, 1691, 1639, 1520, 1462, 1402, 1254, 1144 cm⁻¹; [α]_(D) ²⁵ + 28.4 ± 0.7° (c = 1.008%, MeOH); Anal. (C₂₅H₃₂N₂O₅S.0.2H₂O) Calcd. (%): C, 63.05; H, 6.86; N, 5.88; S, 6.73 Found (%): C, 63.01; H, 6.78; N, 5.84; S, 6.70 IIc-115 ¹H-NMR (CDCl₃) δ 0.97 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.25 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.41 (3H, m), 2.46 (3H, s), 2.53 (3H, s), 3.47-3.58 (2H, m), 4.02 (2H, s), 4.35 (1H, m), 6.22 (1H, d, J = 8.4 Hz), 7.05 (1H, s), 7.83 (1H, s), 7.93 (1H, s); IR (CHCl₃) 3508, 3440, 1780, 1732, 1649, 1514, 1242, 1126 cm⁻¹; [α]_(D) ²⁵ + 30.4 ± 0.7° (c = 1.017, MeOH) Anal. (C₂₆H₃₅NO₄S.0.2H₂O) Calcd. (%): C, 67.71; H, 7.74; N, 3.01; S, 6.95 Found (%): C, 67.37; H, 7.91; N, 2.95; S, 6.79 IIc-128 ¹H-NMR (CDCl₃) δ 0.99 (1H, d, J = 10.5 Hz), 1.12 (3H, s), 1.25 (each 3H, s), 1.41-2.41 (12H, m), 3.49 (2H, t, J = 7.5 Hz), 3.99 (2H, s), 4.32 (2H, s), 5.05 (2H, br s), 6.29 (1H, d, J = 9.0 Hz), 7.48 (1H, d, J = 10.2 Hz), 7.67 (1H, s), 8.09 (1H, d, J = 8.7 Hz); IR (CHCl3) 3579, 3438, 3192, 2924, 1730, 1635, 1518, 1433, 1277 cm⁻¹; [α]_(D) ²⁶ + 22.4 ± 0.6° (c = 1.014%, MeOH); Anal. (C₂₄H₃₀NO₅SF.0.6H₂O) Calcd. (%): C, 60.77; H, 6.63; N, 2.95; S, 6.76; F, 4.00 Found (%): C, 60.72; H, 6.35; N, 2.85; S, 6.58; F, 4.01  

TABLE 51 Compound No. Physical property IIc-129 ¹H-NMR (CDCl₃) δ 0.97 (1H, d, J = 10.5 Hz), 1.15 (3H, s), 1.25 (3H, s), 1.44-2.40 (12H, m), 3.55 (2H, t, J = 6.3 Hz), 3.98 (3H, s), 4.02 (2H, s), 4.32 (1H, m), 6.19 (1H, d, J = 6.6 Hz), 7.62 (1H, d, J = 10.5 Hz), 7.69 (1H, s), 8.07 (1H, d, J = 8.1 Hz); IR (CHCl₃) 3444, 2924, 1780, 1732, 1649, 1512, 1466, 1415, 1263, 1225 cm⁻¹; [α]_(D) ²⁵ + 22.5 ± 0.6° (c = 1.006%, MeOH); Anal. (C₂₅H₃₂NO₅SF.0.2H₂O) Calcd. (%): C, 62.40; H, 6.79; N, 2.91; S, 6.66; F, 3.95 Found (%): C, 62.32; H, 6.74; N, 2.86; S, 6.72; F, 3.88 IIc-135 ¹H-NMR (CDCl₃—DMSO—d₆) δ 0.93 (1H, d, J = 10.2 Hz), 1.16 (3H, s), 1.23 (3H, s), 1.42-1.74 (7H, m), 1.91-2.02 (2H, m), 2.20-2.36 (3H, m), 3.52 (2H, t, J = 6.9 Hz), 4.00 (2H, s), 4.27 (1H, m), 6.34 (1H, br d, J = 8.4 Hz), 7.35 (1H, dd, J = 2.1, 8.7 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.96 (1H, d, J = 2.1 Hz), 8.11 (1H, s); IR (nujol) 3440, 1724, 1635, 1556, 1298, 1252, 1173, 1128 cm⁻¹; [α]_(D) ²⁴ + 17.1 ± 0.6° (c = 1.004, MeOH) IIe-04 mp 79-81° C.; ¹H-NMR (CDCl₃) δ 0.95 (1H, d, J = 9.9 Hz), 1.21 (3H, s), 1.23 (3H, s), 1.36-1.88 (8H, m), 2.00 (1H, m), 2.10-2.38 (3H, m), 2.65 (2H, t, J = 6.9 Hz), 3.17 (1H, d, J = 14.7 Hz), 3.22 (1H, d, J = 14.7 Hz), 4.27 (1H, m), 6.18 (1H, d, J = 9.0 Hz), 7.32-7.36 (2H, m), 7.86 (1H, dd, J = 1.5, 2.4 Hz); IR (Nujol) 3396, 3361, 3109, 3076, 2617, 1720, 1631, 1593, 1543, 1508, 1234, 1221, 1124 cm⁻¹; [α]_(D) ²⁶ + 29.4 ± 0.7° (c = 1.005, MeOH); Anal. (C₂₀H₂₉NO₃S₂) Calcd. (%): C, 60.72; H, 7.39; N, 3.54; S, 16.21 Found (%): C, 60.73; H, 7.45; N, 3.61; S, 16.17 IIe-17 mp 176-178° C.; ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 9.9 Hz), 1.13 (3H, s), 1.25 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.41 (3H, m), 2.66 (2H, t, J = 6.9 Hz), 3.15 (1H, d, J = 14.7 Hz), 3.21 (1H, d, J = 14.7 Hz), 4.36 (1H, m), 6.24 (1H, d, J = 8.7 Hz), 7.40 (1H, dt, J = 1.2, 7.5 Hz), 7.45 (1H, dt, J = 1.2, 7.5 Hz), 7.85 (1H, s), 7.87 (1H, dd, J = 1.2, 7.5 Hz), 8.30 (1H, dd, 1.2, 7.5 Hz); IR (Nujol) 3425, 3091, 3059, 2632, 1726, 1608, 1522, 1261, 1250, 1215, 1126 cm⁻¹; [α]_(D) ²⁶ + 34.0 ± 0.7° (c = 1.002, MeOH); Anal. (C₂₄H₃₁NO₃S₂) Calcd. (%): C, 64.68; H, 7.01; N, 3.14; S, 14.39 Found (%): C, 64.48; H, 7.01; N, 3.15; S, 14.25 IIe-20 mp 117-118° C.; ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 10.5 Hz), 1.14 (3H, s), 1.26 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.42 (3H, m), 2.49 (3H, s), 2.66 (2H, t, J = 6.9 Hz), 3.16 (1H, d, J = 14.7 Hz), 3.21 (1H, d, J = 14.7 Hz), 4.35 (1H, m), 6.23 (1H, d, J = 8.7 Hz), 7.23 (1H, dd, J = 1.2, 8.4 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.82 (1H, s), 8.11 (1H, d, J = 1.2 Hz; IR (Nujol) 3348, 1726, 1597, 1537, 1255, 1219 cm⁻¹; [α]_(D) ²⁶ + 31.9 ± 0.7° (c = 1.002, MeOH); Anal. (C₂₅H₃₃NO₃S₂) Calcd. (%): C, 65.32; H, 7.24; N, 3.05; S, 13.95 Found (%): C, 65.15; H, 7.05; N, 3.10; S, 13.93 IIe-21 mp 170-172° C.; ¹H-NMR (d₆—DMSO) δ 0.84 (1H, d, J = 9.9 Hz), 1.11 (3H, s), 1.18 (3H, s), 1.28-1.60 (7H, m), 1.94 (1H, m), 2.12-2.34 (6H, m), 2.55 (2H, t, J = 7.2 Hz), 3.17 (2H, s), 3.97 (1H, m), 6.79 (1H, d, J = 7.8 Hz), 7.24 (1H, t, J = 7.8 Hz), 7.78 (1H, d, J = 7.8 Hz), 7.98 (1H, d, J = 6.6 Hz), 8.18 (1H, s), 10.39 (1H, br), 12.46 (1H, br); IR (Nujol) 3357, 3246, 32613, 1693, 1595, 1574, 1541, 1469, 1296, 1228 cm⁻¹; [α]_(D) ²⁷ + 38.7 ± 0.80 (c = 1.004, MeOH); Anal. (C₂₄H₃₁NO₄S₂) Calcd. (%): C, 62.44; H, 6.77; N, 3.03; S, 13.89 Found (%): C, 62.25; H, 6.86; N, 3.08; S, 13.60  

TABLE 52 Compound No. Physical property IIe-22 ¹H-NMR (CDCl₃) δ 0.93 (1H, d, J = 10.2 Hz), 1.10 (3H, s), 1.23 (3H, s), 1.36-1.92 (8H, m), 1.99 (1H, m), 2.16-2.39 (3H, m), 2.56 (2H, t, J = 7.2 Hz), 3.13 (2H, s), 4.32 (1H, m), 6.35 (1H, d, J = 9.0 Hz), 6.95 (1H, dd, J = 2.1, 9.0 Hz), 7.24 (1H, t, J = 2.1 Hz), 7.51 (1H, s), 8.03 (1H, d, J = 9.0 Hz); IR (KBr) 3361, 2661, 1707, 1603, 1523, 1468, 1236 cm⁻¹; [α]_(D) ²⁶ + 23.2 ± 0.6° (c = 1.015, MeOH); Anal. (C₂₄H₃₁NO₄S₂.0.4H₂O) Calcd. (%): C, 61.48; H, 6.84; N, 2.99; S, 13.68 Found (%): C, 61.51; H, 6.74; N, 3.01; S, 13.67 IIe-24 ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.5 Hz), 1.15 (3H, s), 1.26 (3H, s), 1.40-1.92 (8H, m), 2.03 (1H, m), 2.18-2.42 (3H, m), 2.64 (2H, t, J = 7.2 Hz), 3.19 (2H, s), 4.29 (1H, m), 6.59 (1H, d, J = 8.4 Hz), 6.92 (1H, dd, J = 2.1, 6.6 Hz), 7.31 (1H, t, J = 2.1 Hz), 7.32 (1H, t, J = 6.6 Hz), 7.69 (1H, s), 12.22 (1H, s); IR (CHCl₃) 3508, 3452, 2683, 1711, 1624, 1585, 1562, 1523, 1456, 1271, 1227, 1217, 1205 cm⁻¹; [α]_(D) ²⁶ + 34.1 ± 0.7° (c = 1.005, MeOH); Anal. (C₂₄H₃₁NO₄S) Calcd. (%): C, 62.44; H, 6.77; N, 3.03; S, 13.89 Found (%): C, 62.48; H, 6.86; N, 3.03; S, 13.63 IIe-28 mp 197-199° C.; ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 10.5 Hz), 1.14 (3H, s), 1.25 (3H, s), 1.40-1.92 (8H, m), 2.02 (1H, m), 2.18-2.41 (3H, m), 2.66 (2H, t, J = 6.9 Hz), 3.16 (1H, d, J = 15.0 Hz), 3.21 (1H, d, J = 15.0 Hz), 4.33 (1H, m), 6.19 (1H, d, J = 9.3 Hz), 7.16 (1H, td, J = 2.4, 8.7 Hz), 7.78 (1H, dd, J = 4.8, 8.7 Hz), 7.88 (1H, s), 8.07 (1H, dd, J = 2.4, 10.2 Hz); IR (Nujol) 3423, 3087, 2636, 1728, 1606, 1523, 1444, 1433, 1248, 1203, 1128 cm⁻¹; [α]_(D) ²⁶ + 31.0 ± 0.7° (c = 1.013, MeOH); Anal. (C₂₄H₃₀FNO₃S₂.0.1AcOEt) Calcd. (%): C, 62.03; H, 6.57; F, 4.02; N, 2.96; S, 13.57 Found (%): C, 61.84; H, 6.48; F, 3.96; N, 2.98; S, 13.56 IIe-34 mp 143-144° C.; ¹H-NMR (CDCl₃) δ 0.98 (1H, d, J = 10.2 Hz), 1.17 (3H, s), 1.24 (3H, s), 1.40-1.96 (8H, m), 2.02 (1H, m), 2.19-2.41 (3H, m), 2.64 (2H, t, J = 7.2 Hz), 3.15 (1H, d, J = 15.0 Hz), 3.20 (1H, d, J = 15.0 Hz), 4.41 (1H, m), 6.53 (1H, d, J = 8.7 Hz), 7.38 (1H, d, J = 5.4 Hz), 7.43 (1H, t, J = 7.8, Hz), 7.43 (1H, t, J = 7.8 Hz), 7.55 (1H, dd, J = 1.2, 7.8 Hz), 7.59 (1H, d, 5.4 Hz), 7.96 (1H, dd, J = 1.2, 7.8 Hz); IR (Nujol) 3421, 3402, 2625, 1712, 1618, 1579, 1529, 1250, 1215, 1120 cm⁻¹; [α]_(D) ²⁶ + 48.2 ± 0.9° (c = 1.016, MeOH); Anal. (C₂₄H₃₁NO₃S₂) Calcd. (%): C, 64.68; H, 7.01; N, 3.14; S, 14.39 Found (%): C, 64.49; H, 6.85; N, 3.16; S, 14.12 IIe-54 ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 10.2 Hz), 1.14 (3H, s), 1.24 (3H, s), 1.41-2.40 (12H, m), 2.64 (1H, t, J = 7.2 Hz), 3.19 (2H, s), 4.33 (1H, m), 6.14 (1H, d, J = 8.7 Hz), 7.12 (1H, dt, J = 6.0, 2.4 Hz), 7.25 (1H, dd, J = 8.4, 2.4 Hz), 7.81 (1H, dd, J = 8.4, 6.0 Hz), 8.09 (1H, s); IR (CHCl₃) 3446, 2674, 1710, 1654, 1563, 1506, 1490, 1257, 1220, 1205 cm⁻¹; [α]_(D) ^(26.0) + 22.8 ± 1.2° (c = 0.510, MeOH); Anal. (C₂₄H₃₀FNO₄S.0.2H₂O) Calcd. (%): C, 63.89; H, 6.79; F, 4.21; N, 3.10; S, 7.11 Found (%): C, 63.83; H, 6.93; F, 4.02; N, 3.18; S, 7.15  

TABLE 53 Compound No. Physical property IIf-28 ¹H-NMR (CDCl₃) δ 0.96 (1H, d, J = 9.9 Hz), 1.13 (3H, s), 1.25 (3H, s), 1.42-1.86 (9H, m), 2.02 (1H, m), 2.20-2.39 (4H, m), 4.31 (1H, m), 6.01 (1H, d, J = 8.7 Hz), 7.16 (1H, dt, J = 2.4, 9.0 Hz), 7.77 (1H, dd, J = 4.5, 9.0 Hz), 7.84 (1H, s), 8.08 (1H, dd, J = 2.4, 10.2 Hz); IR (CHCl₃) 3516, 3444, 1709, 1653, 1603, 1564, 1514, 1471, 1433, 1250, 1142 cm⁻¹; [α]_(D) ²⁵ + 33.6 ± 0.7° (c = 1.007, MeOH) Anal. (C₂₃H₂₈FNO₃S.0.2H₂O) Calcd. (%): C, 65.60; H, 6.80; N, 3.33; F, 4.51; S, 7.61 Found (%): C, 65.70; H, 6.70; N, 3.28; F, 4.32; S, 7.56 IIf-84 ¹H-NMR (CDCl₃) δ 0.95 (1H, d, J = 9.9 Hz), 1.10 (3H, s), 1.25 (3H, s), 1.32 (3H, t, d = 7.2 Hz), 1.44-1.86 (9H, m), 2.00 (1H, m), 2.21- 2.39 (4H, m), 2.24 (2H, q, J = 7.2 Hz), 4.30 (1H, m), 6.15 (1H, m), 7.65 (1H, br d, J = 8.4 Hz), 7.76 (1H, d, J = 8.4 Hz), 7.78 (1H, s), 8.18 (1H, br s); IR (CHCl₃) 3510, 3437, 1713, 1651, 1606, 1570, 1514, 1441, 1319, 1225, 1207, 1169, 1155, 1080, 1066 cm⁻¹; [α]_(D) ²⁴ + 26.3 ± 0.7° (c = 1.009, MeOH) Anal. (C₂₆H₃₄N₂O₅S.0.4H₂O) Calcd. (%): C, 63.24; H, 7.10; N, 5.67; S, 6.49 Found (%): C, 63.35; H, 6.88; N, 5.55; S, 6.34  

The compounds prepared in Examples above were tested for determining the in vivo and in vitro activities according to the method as shown in Experimental examples below.

Experiment 1 Binding Activity to PGD₂ Receptor

(1) Preparation of Human Platelet Membrane Fraction

Blood was collected using a plastic syringe containing 3.8% sodium citrate from the vein of healthy volunteers (adult male and female), then put into a plastic test tube and mixed by slow-reversion. The sample was then centrifuged at 1800 rpm, for 10 min at room temperature, and the supernatant containing PRP (platelet-rich plasma) was collected. The PRP was re-centrifuged at 2300 rpm, for 22 min at room temperature to obtain platelets. The platelets were homogenized using a homogenizer (Ultra-Turrax) followed by centrifugation 3 times at 20,000 rpm, 10 min at 4° C. to obtain a platelet membrane fraction. After protein determination, the membrane fraction was adjusted to 2 mg/ml and preserved in a refrigerator at −80° C. until using for the binding test.

(2) Binding to PGD₂ Receptor

To a binding-reaction solution (50 mM Tris/HCl, pH 7.4, 5 mM MgCl₂) (0.2 ml) were added the human platelet membrane fraction (0.1 mg) and 5 nM [³H]PGD₂ (115 Ci/mmol), and the mixture was reacted at 4° C. for 90 min. After the reaction, the mixture was filtered through a glass fiber filter paper and washed several times with cooled physiological saline, then the radioactivity retained on the filter paper was measured. The specific-binding ratio was calculated by subtracting the non-specific binding ratio which is the radioactivity similarly measured in the presence of 10 μM PGD₂ from the total binding. The inhibitory activity of each compound was expressed as the concentration required for 50% inhibition (IC₅₀), which was determined by depicting a substitution curve by plotting the binding ratio (%) in the presence of each compound, where the binding ratio in the absence of a test compound is 100%.

Experiment 2 Evaluation of Antagonistic Activity Against PGD₂ Receptor Using Human Platelet

Peripheral blood was collected from a healthy volunteer using a syringe in which 1/9 volume of a citric acid/dextrose solution was previously added. The sample was subjected to centrifugation at 1200 rpm for 10 min to obtain the supernatant (PRP: platelet rich plasma). The resultant PRP was washed 3 times with a washing buffer and the number of platelets was counted with a micro cell counter. A suspension adjusted to contain the platelets at a final concentration of 5×10⁸/ml was warmed at 37° C., then subjected to the pre-treatment with 3-isobutyl-1-methylxanthine (0.5 mM) for 5 min. To the suspension was added a test compound diluted at various concentration, and 10 minutes later, 0.1 μM PGD₂ was added to induce the reaction 2 minutes later, hydrochloric acid was added to terminate the reaction. The platelet was destroyed with an ultrasonic homogenizer. After centrifugation, the cAMP in the supernatant was determined by radioimmunoassay. PGD₂ receptor antagonism of a drug was evaluated as follows: the inhibition rate regarding cAMP increased by the addition of PGD₂ was determined at each concentration, and the concentration of the drug required for 50% inhibition (IC₅₀) was calculated.

The results of Experiment 1 and 2 are shown below.

TABLE 54 Binding activity to PGD₂ Inhibitory activity for the receptor in human platelet increase of cAMP caused by Compound membrane fraction PGD₂ in human platelet No. IC₅₀ (μM) IC₅₀ (μM) Ia-17 0.011 Ia-20 0.017 Ia-65 0.018 Ic-22 0.010 Ic-23 0.01 Ic-52 0.074 0.01 IIa-4 0.019 IIa-17 0.015 IIa-22 0.0037 IIa-23 0.033 0.0025 IIa-28 0.016 IIa-34 0.014 IIa-52 0.0037 IIa-54 0.015 IIa-66 0.017 IIc-4 0.018 IIc-17 0.0054 IIc-20 0.015 IIc-22 0.0046 IIc-23 0.0095 0.0049 IIc-24 0.013 IIc-28 0.013 IIc-34 0.011 IIc-52 0.0035 0.0082 IIc-81 0.008 IIc-86 0.008 IIc-96 0.017 IIc-97 0.011 IIc-99 0.006 IIc-128 0.005 IIc-129 0.018 IIc-135 0.003 IIe-22 0.0048 IIe-24 0.0057 IIe-28 0.017 IIe-34 0.019 IIf-84 0.020   Experiment 3 Change of Plasma Concentration of Drug in Rat

Compound (0.5 to 2 mg/kg) was administered intravenously to Jcl-SD male rats. The concentration of the unchanged compound was measured at 2, 5, 15, 30, 60, 120, and 240 min after the administration by the use of HPLC (determination limit; 0.05 μg/ml) and LC/MS/MS (determination limit; 0.001 μg/ml) and the half life of the disappearance was calculated.

 

TABLE 55 Half life of the Compound No. disappearance (min) Reference compound 1 8.0 IIa-4  21.6 IIc-4  44.3 IIe-4  40.0 Reference compound 2 17.0 IIa-34 34.6 IIc-34 66.7 Reference compound 3 8.7 IIa-52 16.7 IIc-52 23.4  

INDUSTRIAL APPLICABILITY

The compound of the present invention represented by the formula (I) having an antagonistic activity against PGD₂ receptor, is metabolically stable, and is useful in the improvement of conditions due to excessive production of PGD₂. 

1. A compound represented by the formula (I):

  wherein

  R¹ is optionally substituted heteroaryl; R² is hydrogen or alkyl; R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; R⁴ is hydrogen or alkyl; X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 2. A compound as described in claim 1, wherein

  is

  a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 3. A compound as described in claim 1, wherein R¹ is heteroaryl which may be substituted with a group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO₂—, —O—C(═O)—, —C(═O)—O—, —SO₂—, —CH₂—O—, —CH₂—NH—C(═O)—, —CH₂—NH—C(═O)—O—, —CH₂—NH—SO₂— or —CH₂—C(O)— and Z² is alkyl or optionally substituted amino; carboxy; halogen; hydroxy; or nitro, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 4. A compound as described in claim 1, wherein R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; R⁴ is hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 5. A compound as described in claim 4, wherein R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴; R⁴ is hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 6. A pharmaceutical composition comprising an auxiliary component and a compound of Formula (I):

  wherein

  R¹ is optionally substituted heteroaryl; R² is hydrogen or alkyl; R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; R⁴ is hydrogen or alkyl; X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 7. A method for treating nasal blockage, allergic conjunctivitis or allergic rhinitis, which comprises administrating a compound of Formula (I):

  wherein

  R¹ is optionally substituted heteroaryl; R² is hydrogen or alkyl; R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; R⁴ is hydrogen or alkyl; X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvent thereof.
 8. A method of making a pharmaceutical composition for treating nasal blockage, allergic conjunctivitis or allergic rhinitis, comprising introducing to an auxiliary component a compound of claim
 1. 9. A pharmaceutical composition of claim 6, wherein

  is

  a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 10. A pharmaceutical composition of claim 6, wherein R¹ is heteroaryl which may be substituted with a group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO₂—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO₂—, —CH₂—O—, —CH₂—NH—C(═O)—, —CH₂—NH—C(═O)—O—, —CH₂—NH—SO₂— or —CH₂—C(O)— and Z² is alkyl or optionally substituted amino; carboxy; halogen; hydroxy; or nitro, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 11. A pharmaceutical composition of claim 6, wherein R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; R⁴ hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 12. A pharmaceutical composition of claim 11, wherein R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴; R⁴ is hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 13. A method of claim 7, wherein

  is

  a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 14. A method of claim 7, wherein R¹ is heteroaryl which may be substituted with a group of the formula: -Z¹-Z² wherein Z¹ is a bond, —O—, —S—, —NH—, —NH—C(═O)—, —NH—C(═O)—O—, —NH—SO₂—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —SO₂—, —CH₂—O—, —CH₂—NH—C(═O)—, —CH₂—NH—C(═O)—O—, —CH₂—NH—SO₂— or —CH₂—C(O)— and Z² is alkyl or optionally substituted amino; carboxy; halogen; hydroxy; or nitro, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 15. A method of claim 7, wherein R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴, —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴, —CH₂—CH═CH—CH₂—X¹—CH₂—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—COOR⁴; R⁴ is hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof.
 16. A method of claim 15, wherein R³ is —CH₂—CH₂—CH₂—CH₂—CH═CH—COOR⁴ or —CH₂—CH₂—CH₂—CH₂—X¹—CH₂—COOR⁴; R⁴ is hydrogen; and X¹ is —O— or —S—, a prodrug, a pharmaceutically acceptable salt or a solvate thereof. 